US20140135328A1 - Substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals - Google Patents

Substituted 3-heteroaroylamino-propionic acid derivatives and their use as pharmaceuticals Download PDF

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US20140135328A1
US20140135328A1 US14/157,703 US201414157703A US2014135328A1 US 20140135328 A1 US20140135328 A1 US 20140135328A1 US 201414157703 A US201414157703 A US 201414157703A US 2014135328 A1 US2014135328 A1 US 2014135328A1
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alkyl
phenyl
group
amino
carbonyl
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Sven Ruf
Thorsten SADOWSKI
Klaus Wirth
Herman Schreuder
Christian Buning
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Sanofi SA
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Definitions

  • the present invention relates to compounds of the formula I,
  • A, D, E, L, G, R 10 , R 30 , R 40 , R 50 and R 60 have the meanings indicated below, which are valuable pharmaceutical active compounds. They are inhibitors of the protease cathepsin A, and are useful for the treatment of diseases such as atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases, for example.
  • the invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.
  • cathepsin A The interaction of cathepsin A with these glycosidases is essential for their correct routing to the lysosome and protects them from intralysosomal proteolysis.
  • a deficiency of cathepsin A resulting from various mutations in the ctsa gene leads to a secondary deficiency of beta-galactosidase and neuraminidase that is manifest as the autosomal recessive lysosomal storage disorder galactosialidosis (cf. A. d'Azzo et al., in “The Metabolic and Molecular Bases of Inherited Disease”, vol. 2 (1995), 2835-2837).
  • mice carrying a catalytically inactivating mutation in the ctsa gene do not develop signs of the human disease galactosialidosis (R. J. Rottier et al., Hum. Mol. Genet. 7 (1998), 1787-1794; V. Seyrantepe et al., Circulation 117 (2008), 1973-1981).
  • Cathepsin A displays carboxypeptidase activity at acidic pH and deamidase and esterase activities at neutral pH against various naturally occurring bioactive peptides.
  • cathepsin A converts angiotensin I to angiotensin 1-9 and bradykinin to bradykinin 1-8, which is the ligand for the bradykinin B1 receptor. It hydrolyzes endothelin-1, neurokinin and oxytocin, and deamidates substance P (cf. M. Hiraiwa, Cell. Mol. Life. Sci. 56 (1999), 894-907).
  • High cathepsin A activity has been detected in urine, suggesting that it is responsible for tubular bradykinin degradation (M.
  • Sohma et al. Pediatr. Neurol. 20 (1999), 210-214). It is upregulated during differentiation of monocytes to macrophages (N. M. Stamatos et al., FEBS J. 272 (2005), 2545-2556). Apart from structural and enzymatic functions, cathepsin A has been shown to associate with neuraminidase and an alternatively spliced beta-galactosidase to form the cell-surface laminin and elastin receptor complex expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes and certain cancer cell types (A. Hinek, Biol. Chem. 377 (1996), 471-480).
  • cathepsin A for the regulation of local bradykinin levels has been demonstrated in animal models of hypertension.
  • Pharmacological inhibition of cathepsin A activity increased renal bradykinin levels and prevented the development of salt-induced hypertension (H. Ito et al., Br. J. Pharmacol. 126 (1999), 613-620).
  • This could also be achieved by antisense oligonucleotides suppressing the expression of cathepsin A (I. Hajashi et al., Br. J. Pharmacol. 131 (2000), 820-826).
  • beneficial effects of bradykinin have been demonstrated in various further cardiovascular diseases and other diseases (cf. J. Chao et al., Biol. Chem.
  • cathepsin A inhibitors therefore include atherosclerosis, heart failure, cardiac infarction, cardiac hypertrophy, vascular hypertrophy, left ventricular dysfunction, in particular left ventricular dysfunction after myocardial infarction, renal diseases such as renal fibrosis, renal failure and kidney insufficiency; liver diseases such as liver fibrosis and liver cirrhosis, diabetes complications such as nephropathy, as well as organ protection of organs such as the heart and the kidney.
  • cathepsin A inhibitors can prevent the generation of the bradykinin B1 receptor ligand bradykinin 1-8 (M. Saito et al., Int. J. Tiss. Reac. 17 (1995), 181-190). This offers the opportunity to use cathepsin A inhibitors for the treatment of pain, in particular neuropathic pain, and inflammation, as has been shown for bradykinin B1 receptor antagonists (cf. F. Marceau et al., Nat. Rev. Drug Discov. 3 (2004), 845-852).
  • Cathepsin A inhibitors can further be used as anti-platelet agents as has been demonstrated for the cathepsin A inhibitor ebelactone B, a propiolactone derivative, which suppresses platelet aggregation in hypertensive animals (H. Ostrowska et al., J. Cardiovasc. Pharmacol. 45 (2005), 348-353).
  • cathepsin A can stimulate the amiloride-sensitive epithelial sodium channel (ENaC) and is thereby involved in the regulation of fluid volumes across epithelial membranes (cf. C. Planes et al., Curr. Top. Dev. Biol. 78 (2007), 23-46).
  • EaC amiloride-sensitive epithelial sodium channel
  • respiratory diseases can be ameliorated by the use of cathepsin A inhibitors, such as cystic fibrosis, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections and lung carcinoma.
  • Cathepsin A modulation in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
  • amine derivatives which modulate the activity of steroid nuclear receptors, are described which carry on the nitrogen atom of the amine function a heteroaroyl group and a further group which is defined very broadly.
  • beta-amino acid derivatives which carry an acyl group on the beta-amino group and are inhibitors of matrix metalloproteases and/or tumor necrosis factor.
  • pyrazoloylamino-substituted carboxylic acid derivatives which, however, additionally carry a carboxylic acid derivative group on the carbon atom carrying the pyrazoloylamino group.
  • Other pyrazoloylamino-substituted compounds, in which the nitrogen atom of the amino group is connected to a ring system and which are inhibitors of the blood clotting enzymes factor Xa and/or factor Vila are described in WO 2004/056815.
  • a subject of the present invention is a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them,
  • A is chosen from the series consisting of C(R 1 ) and N; D is chosen from the series consisting of C(R 2 ) and N; E is chosen from the series consisting of C(R 3 ) and N; L is chosen from the series consisting of C(R 4 ) and N; where at least one and at most two of A, D, E or L is N; G is chosen from the series consisting of R 71 —O—C(O)—, R 72 —N(R 73 )—C(O)— and tetrazol-5-yl; R 1 is chosen from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, HO—, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S(O) m — and NC—; R 2 is chosen from the series consisting of hydrogen, halogen, (C 1 -C 7 )-alkyl, (C 1 -(
  • R 2 and R 3 are —NH—CH ⁇ N—;
  • R 1 , R 2 , R 3 , R 4 or R 10 is a cyclic substituent
  • R 11 is chosen from the series consisting of hydrogen, R 14 , (C 3 -C 7 )-cycloalkyl, Ar and Het 3
  • R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen and R 15
  • R 14 is (C 1 -C 10 )-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, R 16 —O—, oxo, (C 3 -C 7 )-cycloalkyl, Ar, Het 1 , Het 3 , NC—, H 2 N—C(O)—, (C 1 -C 4 )-alkyl-NH—C(O)—, di((C 1 -C 4 )-alkyl)N—C(O)—, Het 1 -C(O)—, (C
  • R 16 is (C 1 -C 6 )-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of HO—, (C 1 -C 4 )-alkyl-O— and NC—;
  • R 30 is chosen from the series consisting of R 31 , (C 3 -C 7 )-cycloalkyl, R 32 —C u H 2u — and Het 3 -C u H 2u —, wherein u is an integer chosen from the series consisting of 0, 1, 2 and 3;
  • R 31 is (C 1 -C 10 )-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S(O) m — and NC—;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring
  • Het 1 is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one or two identical or different further ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O—, oxo and NC—;
  • Het 2 is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het 2 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O—;
  • Het 3 independently of each other group Het 3 , is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (C 1 -C 4 )-alkyl and oxo;
  • Het 4 independently of each other group Het 4 , is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O—, oxo and NC—;
  • n independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2; wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (C 1 -C 4 )-alkyl; wherein all alkyl, C s H 2s , C u H 2u , (CH 2 ) x and (CH 2 ) y groups, independently of each other, and independently of any other substituents, are optionally substituted by one or more fluorine substituents.
  • Alkyl groups i.e. saturated hydrocarbon residues
  • the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or 1, 2, 3, 4, 5, 6, 7 or 8, or 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, or 1, for example.
  • a (C 1 -C 10 -alkyl group present in the compounds of the formula I is a (C 1 -C 8 )-alkyl group, in another embodiment a (C 1 -C 6 )-alkyl group, in another embodiment a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a (C 2 -C 3 )-alkyl group, in another embodiment a methyl group.
  • a (C 1 -C 8 )-alkyl group present in any position of the compounds of the formula I is a (C 1 -C 6 )-alkyl group, in another embodiment a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a (C 2 -C 3 )-alkyl group, in another embodiment a methyl group, where any (C 1 -C 8 )-alkyl group present in the compounds of the formula I can independently of each other (C 1 -C 8 )-alkyl group be a group of any of these embodiments.
  • a (C 1 -C 6 )-alkyl group present in any position of the compounds of the formula I is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a (C 2 -C 3 )-alkyl group, in another embodiment a methyl group, where any (C 1 -C 6 )-alkyl group present in the compounds of the formula I can independently of each other (C 1 -C 6 )-alkyl group be a group of any of these embodiments.
  • a (C 1 -C 4 )-alkyl group present in any position of the compounds of the formula I is a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a (C 2 -C 3 )-alkyl group, in another embodiment a methyl group, where any (C 1 -C 4 )-alkyl group present in the compounds of the formula I can independently of each other (C 1 -C 4 )-alkyl group be a group of any of these embodiments.
  • alkyl groups are methyl, ethyl, propyl groups including propyl (i.e.
  • n-propyl and isopropyl
  • butyl groups including butyl (i.e. n-butyl), sec-butyl, isobutyl and tert-butyl
  • pentyl groups including pentyl (i.e. n-pentyl), 1-methylbutyl, isopentyl, neopentyl and tert-pentyl
  • hexyl groups including hexyl (i.e. n-hexyl), 3,3-dimethylbutyl and isohexyl
  • heptyl groups including heptyl (i.e. n-heptyl)
  • octyl groups including octyl (i.e.
  • alkyl-O— groups are methoxy, ethoxy, propoxy (i.e. n-propoxy), isopropoxy, butoxy (i.e. n-butoxy), isobutoxy, tert-butoxy, pentoxy (i.e. n-pentoxy).
  • alkyl-S(O) m — examples are methylsulfanyl-(CH 3 —S—), methanesulfinyl-(CH 3 —S(O)—), methanesulfonyl(CH 3 —S(O) 2 —), ethylsulfanyl-(CH 3 —CH 2-S —), ethanesulfinyl-(CH 3 —CH 2 —S(O)—), ethanesulfonyl(CH 3 —CH 2 —S(O) 2 —), 1-methylethylsulfanyl-((CH 3 ) 2 CH—S—), 1-methylethanesulfinyl-((CH 3 ) 2 CH—S(O)—), 1-methylethanesulfonyl((CH 3 ) 2 CH—S(O) 2 —).
  • the number m is chosen from 0 and 2, wherein all numbers m are independent of each other and can be identical or different. In another embodiment the number m in any of its occurrences is, independently of its meaning in other occurrences, 0. In another embodiment the number m in any of its occurrences is, independently of its meaning in other occurrences, 2.
  • a substituted alkyl group can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound.
  • an individual carbon atom in any alkyl group in the compounds of the formula I, as well as in other groups such as cycloalkyl groups and heterocyclic groups, for example, independently of any other carbon atom does not carry more than one substituent which is bonded via an oxygen atom, nitrogen atom or sulfur atom, such as HO—, (C 1 -C 4 )-alkyl-O— or (C 1 -C 4 )-alkyl-S(O) m -substituents, for example.
  • An alkyl group which is optionally substituted by one or more fluorine substituents can be unsubstituted, i.e.
  • fluorine substituents not carry fluorine substituents, or substituted, for example by one, two, three, four, five, six, seven, eight, nine, ten or eleven fluorine substituents, or by one, two, three, four, five, six or seven fluorine substituents, or by one, two, three, four or five fluorine substituents, or by one, two or three fluorine substituents, which can be located in any positions.
  • one or more methyl groups can carry three fluorine substituents each and be present as trifluoromethyl groups
  • one or more methylene groups (CH 2 ) can carry two fluorine substituents each and be present as difluoromethylene groups.
  • fluoro-substituted alkyl groups are trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl and heptafluoroisopropyl.
  • fluoro-substituted alkyl-O— groups are trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy.
  • fluoro-substituted alkyl-S(O) m — groups are trifluoromethylsulfanyl-(CF 3 —S—), trifluoromethanesulfinyl-(CF 3 —S(O)—) and trifluoromethanesulfonyl(CF 3 —S(O) 2 —).
  • alkyl groups including the divalent groups C s H 2s , C u H 2u , (CH 2 ) x and (CH 2 ) y .
  • alkyl part of a substituted alkyl group may be regarded as an alkanediyl group.
  • alkanediyl groups can also be linear or branched, the bonds to the adjacent groups can be located in any positions and can start from the same carbon atom or from different carbon atoms, and they can be substituted by fluorine substituents.
  • alkanediyl groups including the groups C s H 2s and C u H 2u and, as far they constitute polymethylene chains
  • the groups (CH 2 ) x are —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH(CH 3 )—CH 2 —, —CH 2 —CH(CH 3 )—, —C(CH 3 ) 2 —CH 2 —, —CH 2 —C(CH 3 ) 2 —CH 2 —, —CH 2 —C(CH 3 ) 2 —.
  • fluoro-substituted alkanediyl groups which can contain one, two, three, four, five or six fluorine substituents, or one, two, three or four fluorine substituents, or one or two fluorine substituents, for example, are —CHF—, —CF 2 — —CF 2 —CH 2 —, —CH 2 —CF 2 —, —CF 2 —CF 2 —, —CF(CH 3 )—, —C(CF 3 ) 2 —, —C(CH 3 ) 2 —CF 2 —, —CF 2 —C(CH 3 ) 2 —.
  • the number of ring carbon atoms in a (C 3 -C 7 )-cycloalkyl group can be 3, 4, 5, 6 or 7.
  • Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • substituents they be unsubstituted, i.e.
  • alkyl substituents not carry alkyl substituents, or substituted, for example by one, two, three or four, or by one or two, identical or different (C 1 -C 4 )-alkyl substituents, for example by methyl groups, which substituents can be located in any positions.
  • alkyl-substituted cycloalkyl groups are 1-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-methylcyclopentyl, 2,3-dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl and 3,3,5,5-tetramethylcyclohexyl.
  • cycloalkyl groups can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by one, two, three, four, five, six, seven, eight, nine, ten or eleven fluorine substituents, or by one, two, three, four, five or six fluorine substituents, or by one, two, three or four fluorine substituents, or by one or two fluorine substituents.
  • the fluorine substituents can be located in any positions of the cycloalkyl group and can also be located in an alkyl substituent on the cycloalkyl group.
  • fluoro-substituted cycloalkyl groups are 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl, 4,4-difluorocyclohexyl and 3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkyl groups can also be substituted simultaneously by fluorine and alkyl.
  • Examples of (C 3 -C 7 )-cycloalkyl-substituted alkyl groups which can represent R 11 or R 30 , for example, are cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-, 2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-, 1-cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-, 2-cyclohexylethyl-, 1-cycloheptylethyl-, 2-cycloheptylethyl-.
  • cycloalkyl groups apply correspondingly to divalent cycloalkyl groups (cycloalkanediyl groups), which can occur in case the two groups R 30 and R 40 together are (CH 2 ), or the two groups R 50 and R 60 together are (CH 2 ) y .
  • the cycloalkyl part of a substituted cycloalkyl group may be regarded as a cycloalkanediyl group.
  • the bonds through which a cycloalkanediyl group is connected to the adjacent groups can be located in any positions and can start from the same ring carbon atom, as in the case of the cycloalkanediyl group which is present if R 30 and R 40 together are (CH 2 ) x or the two groups R 50 and R 60 together are (CH 2 ) y , or from different ring carbon atoms.
  • the substituents can be located in any positions.
  • the divalent substituents —O—CH 2 —O— (methylenedioxy) and —O—CF 2 - ⁇ -(difluoromethylenedioxy) which can be present on phenyl groups and aromatic heterocycles, the two oxygen atoms are bonded to adjacent ring carbon atoms of the phenyl group or the aromatic heterocycle and replace two hydrogen atoms of the parent system.
  • the substituent can be located in the 2-position, the 3-position or the 4-position.
  • the substituents can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position.
  • the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. If a phenyl group carries four substituents, some of which can be fluorine atoms, for example, the substituents can be located in 2,3,4,5-position, 2,3,4,6-position or 2,3,5,6-position.
  • each substituent can be located in any suitable position, and the present invention comprises all positional isomers.
  • the number of substituents in an optionally substituted phenyl group can be one, two, three, four or five.
  • an optionally substituted phenyl group, independently of any other optionally substituted phenyl group in a compound of the formula I carries one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, identical or different substituents, and in another embodiment it is unsubstituted.
  • substituted heterocyclic groups including aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R 32 , R 33 and Ar, saturated and unsaturated 4-membered to 8-membered monocyclic heterocycles which can represent Het 1 , and saturated 4-membered to 7-membered monocyclic heterocycles which can represent Het 2 and Het 3
  • the substituents can be located in any positions and can be present on ring carbon atoms and/or on suitable ring nitrogen atoms.
  • the present invention comprises all positional isomers.
  • the number of substituents which can be present on substituted heterocycles in the compounds of the formula I depends on the ring size, the number and type of the ring heteroatoms and the degree of unsaturation.
  • the number of identical or different substituents on any of the heterocyclic groups in the compounds of the formula I is one, two, three, four or five, in another embodiment one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one.
  • Ring nitrogen atoms which optionally carry a substituent include ring nitrogen atoms in saturated heterocyclic rings other than those via which such a ring is bonded, and the ring nitrogen atom in 5-membered aromatic heterocycles such as pyrrole, imidazole or triazole, which in the parent heterocycle carry a hydrogen atom.
  • the substituents on any such ring nitrogen atoms in heterocyclic groups are chosen from those of the substituents specified in the definition of the respective group which are bonded via a carbon atom, for example from the series consisting of (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl and R 33 , in another embodiment from the series consisting of (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl, in the case of the aromatic heterocycle which can represent R 32 , from the series consisting of (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl in the case of the aromatic heterocycle which can represent R 33 , and are (C 1 -C 6 )-alkyl in the case of the aromatic heterocycle which can represent Ar and (C 1 -C 4 )-alkyl in the case of Het 1 , Het 2 and Het
  • suitable ring nitrogen atoms in heterocyclic groups in the compounds of the formula I in particular aromatic heterocyclic groups such as the heterocyclic groups which can represent R 32 , R 33 and Ar, for example the ring nitrogen atom in a pyridinyl group, can also carry an oxido substituent —O ⁇ and be present as an N-oxide.
  • the ring heteroatoms specified in the definitions of heterocyclic groups in the compounds of the formula I including the aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R 32 , R 33 and Ar and the heterocycles which represent Het 1 , Het 2 , Het 3 and Het 4 can generally be present in any combination and located in any suitable ring positions, provided that the resulting group and the compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound, as mentioned above.
  • two oxygen atoms in any heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions.
  • two ring heteroatoms in any non-aromatic heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions.
  • two ring heteroatoms chosen from the series consisting of N atoms which carry a hydrogen atom or a substituent and are bonded to the adjacent ring atoms by single bonds, O atoms and S atoms in a non-aromatic heterocycle cannot be present in adjacent ring positions.
  • an aromatic heterocycle the choice of ring heteroatoms and their positions is limited by the prerequisite that the ring is aromatic, i.e., it comprises a cyclic system of six delocalized pi electrons.
  • an aromatic monocyclic 6-membered heterocycle only nitrogen atoms can occur as ring heteroatoms
  • an aromatic monocyclic 5-membered heterocycle only one ring heteroatom chosen from the series consisting of O atoms, S atoms and N atoms carrying a hydrogen atom or a substituent
  • An unsaturated heterocycle which can represent Het 1 can be aromatic, for example in the case of a pyrrolyl, imidazolyl or triazolyl group which is bonded via a ring nitrogen atom and can represent Het 1 , or non-aromatic and comprise one or two double bonds within the ring which can be present in any positions.
  • a 4-membered heterocycle representing Het 1 cannot be unsaturated.
  • a heterocyclic group can be bonded via any ring carbon atom or via any suitable ring nitrogen atom, respectively, as indicated in the definition of the respective group.
  • the group Het 1 can be 4-membered, 5-membered, 6-membered or 7-membered or 8-membered.
  • the groups Het 2 and Het 3 can be 4-membered, 5-membered, 6-membered or 7-membered.
  • aromatic heterocycles from any one or more of which the aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R 32 , R 33 and Ar and, as far as applicable, the group Het 1 are chosen in one embodiment of the invention, are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole ([1,3]oxazole), isoxazole ([1,2]oxazole), thiazole ([1,3]thiazole), isothiazole ([1,2]thiazole), [1,2,3]triazole, [1,2,4]triazole, [1,3,4]oxadiazole, pyridine, pyridazine, pyrimidine and pyrazine, which can all be bonded via any ring carbon atom or via any suitable ring nitrogen atom, and which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • Examples of specific residues of aromatic heterocycles from any one or more of which the aromatic, 5-membered or 6-membered monocyclic heterocyclic residue which can represent R 32 , R 33 or Ar and, as far as applicable, the group Het 1 , are chosen in one embodiment of the invention, are pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl (2-thienyl), thiophen-3-yl (3-thienyl), imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isox
  • saturated heterocycles and non-aromatic unsaturated heterocycles from any one or more of which the groups Het 1 , Het 2 , Het 3 and Het 4 are independently of each other chosen in one embodiment of the invention, as far as applicable with regard to the ring size and the degree of saturation, are azetidine, oxetane, thietane, pyrrolidine, 2,5-dihydro-1H-pyrrole, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, 4,5-dihydro-1H-imidazole, [1,3]dioxolane, oxazolidine, thiazolidine, piperidine, 1,2,3,6-tetrahydropyridine, tetrahydropyran, tetrahydrothiopyran, piperazine, [1,3]dioxane, [1,4]dioxane, morpholine,
  • Examples of specific residues of saturated and non-aromatic unsaturated heterocycles, from any one or more of which the groups Het 1 , Het 2 , Het 3 and Het 4 are independently of each other chosen in one embodiment of the invention, as far as applicable with regard to the ring size, the degree of saturation and the kind of the atom via which the residue is bonded are azetidin-1-yl, oxetan-3-yl, thietan-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, pyrazolidin-1-yl, pyrazolidin-4-yl, imidazolidin-1-yl, imi
  • Halogen is fluorine, chlorine, bromine or iodine.
  • halogen in any occurrence in the compounds of the formula I is fluorine, chlorine or bromine, in another embodiment fluorine or chlorine, in another embodiment fluorine.
  • An oxo substituent i.e. an oxygen atom which is bonded via a double bond, when bonded to a carbon atom, replaces two hydrogen atoms on the carbon atom of the parent system to which it is bonded.
  • a CH 2 group is substituted by oxo, it becomes a carbonyl group (C(O), C ⁇ O).
  • An oxo substituent cannot be present on a carbon atom in an aromatic ring.
  • oxo substituents can also be present on a ring sulfur atom in the group Het 1 , in particular if the group Het 1 is saturated, and in the group Het 3 , to give the ring member S(O) (S ⁇ O, i.e. a sulfoxide group), if one oxo substituent is present on the sulfur atom, or the ring member S(O) 2 (S( ⁇ O) 2 , i.e. a sulfone group), if two oxo substituents are present on the sulfur atom.
  • heterocycles which can represent Het 1 and Het 3 and which carry oxo substituent a ring sulfur atom
  • 1,1-dioxo-tetrahydrothiophene, 1-oxo-thiomorpholine and 1,1-dioxo-thiomorpholine may be mentioned, which all are optionally substituted by further substituents such as (C 1 -C 4 )-alkyl substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the present invention comprises all stereoisomeric forms of the compounds of the formula I, for example all enantiomers and diastereomers including cis/trans isomers.
  • the invention likewise comprises mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers including cis/trans isomers, in all ratios.
  • Asymmetric centers contained in the compounds of the formula I, for example in unsubstituted or substituted alkyl groups, can all independently of each other have the S configuration or the R configuration.
  • the invention relates to enantiomers, both the levorotatory and the dextrorotatory antipode, in enantiomerically pure form and essentially enantiomerically pure form, for example with a molar ratio of the two enantiomers of 99:1 or greater, and in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
  • the invention likewise relates to diastereomers in the form of pure and essentially pure diastereomers and in the form of mixtures of two or more diastereomers in all ratios.
  • the invention also comprises all cis/trans isomers of the compounds of the formula I in pure form and essentially pure form, for example with a molar ratio of the cis/trans isomers of 99:1 or greater, and in the form of mixtures of the cis isomer and the trans isomer in all ratios.
  • Cis/trans isomerism can occur in substituted rings.
  • the preparation of individual stereoisomers if desired, can be carried out by resolution of a mixture according to customary methods, for example, by chromatography or crystallization, or by use of stereochemically uniform starting compounds in the synthesis or by stereoselective reactions.
  • a derivatization can be carried out before a separation of stereoisomers.
  • the separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula I or at the stage of an intermediate in the course of the synthesis.
  • the invention also comprises all tautomeric forms of the compounds of the formula I.
  • Physiologically acceptable salts, including pharmaceutically utilizable salts, of the compounds of the formula I generally comprise a nontoxic salt component. They can contain inorganic or organic salt components. Such salts can be formed, for example, from compounds of the formula I which contain an acidic group, for example a carboxylic acid group (hydroxycarbonyl group, HO—C(O)—), and nontoxic inorganic or organic bases. Suitable bases are, for example, alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia, organic amino compounds and quaternary ammonium hydroxides.
  • protonatable, group for example an amino group or a basic heterocycle
  • physiologically acceptable acids for example as salt with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, which in general can be prepared from the compounds of the formula I by reaction with an acid in a solvent or diluent according to customary procedures.
  • the compounds of the formula I simultaneously contain an acidic and a basic group in the molecule, the invention also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned.
  • the present invention also comprises all salts of the compounds of the formula I which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange.
  • the present invention also comprises all solvates of the compounds of the formula I and their salts, including physiologically acceptable solvates, such as hydrates, i.e. adducts with water, and adducts with alcohols like (C 1 -C 4 )-alkanols, as well as active metabolites of compounds of the formula I and prodrugs of the compounds of the formula I, i.e.
  • compounds which in vitro may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds of the formula I, for example compounds which are converted by metabolic hydrolysis into a compound of the formula I, such as compounds in which a carboxylic acid group is present in esterified form or in the form of an amide.
  • the group A is C(R 1 ), in another embodiment A is N, in one embodiment of the invention, the group D is chosen from the series consisting of N, in another embodiment from the series consisting of C(R 2 ), in one embodiment of the invention, the group E is chosen from the series consisting of N, in another embodiment from the series consisting of C(R 3 ), in one embodiment of the invention, the group L is chosen from the series consisting of N, in another embodiment from the series consisting of C(R 4 ), with the proviso that one or two of the groups A, D, E, L is N.
  • the group A is N and the groups D, E and L are C(R 2 ), C(R 3 ) and C(R 4 ).
  • the group D is N and the groups A, E and L are C(R 1 ), C(R 3 ) and C(R 4 ).
  • the group E is N and the groups A, D and L are C(R 1 ), C(R 2 ) and C(R 4 ).
  • the group L is N and the groups A, D and E are C(R 1 ), C(R 2 ) and C(R 3 ).
  • the groups A and D are N and the groups E and L are C(R 3 ) and C(R 4 ).
  • the group A and E is N and the groups D and L are C(R 2 ) and C(R 4 ).
  • the group A and L is N and the groups D and E are C(R 2 ) and C(R 3 ).
  • the group D and E is N and the groups A and L are C(R 1 ) and C(R 4 ).
  • the group D and L is N and the groups A and E are C(R 1 ) and C(R 3 ).
  • the group E and L is N and the groups A and D are C(R 1 ) and C(R 2 ).
  • a compound of the formula I is a compound of any one or more of formulae I-1 to I-7, for example a compound of formula I-1, or a compound of formula I-2, or a compound of formula I-3, or a compound of formula I-4, or a compound of formula I-5, or a compound of formula I-6, or a compound of formula I-7 in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein in the compounds of formulae I-1 to I-7 the groups A, D, E, G, R 1 , R 2 , R 3 , R 10 , R 30 , R 40 , R 50 and R 60 are defined as in the compounds of formula I in general or in any embodiment specified above or below.
  • the group G is chosen from the series consisting of R 71 —O—C(O)—, R 72 —N(R 73 )—C(O)— and tetrazol-5-yl, in another embodiment from the series consisting of R 71 —O—C(O)— and R 72 —N(R 73 )—C(O)—, in another embodiment G is R 71 —O—C(O)—, and in another embodiment G is R 72 —N(R 73 )—C(O)—.
  • the group R 1 is chosen from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, HO—, (C 1 -C 6 )-alkyl-O—, and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-O— and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, HO— and (C 1 -C 6 )-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen, (C 1 -
  • a (C 1 -C 6 )-alkyl group occurring in R 1 is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment it is methyl.
  • the group R 2 is chosen from the series consisting of (C 1 -C 7 )-alkyl and (C 3 -C 7 )-cycloalkyl-C s H 2s —, in another embodiment from the series consisting of (C 3 -C 7 )-cycloalkyl-C s H 2s — and Ar—C s H 2s —, in another embodiment R 2 is (C 1 -C 7 )-alkyl, in another embodiment R 2 is (C 3 -C 7 )-cycloalkyl-C s H 2s —, and in another embodiment R 2 is Ar—C s H 2s —.
  • s is an integer chosen from the series consisting of 0, 1 and 2, in another embodiment from the series consisting of 0 and 1, in another embodiment from the series consisting of 1 and 2, in another embodiment s is 0, and in another embodiment is 1.
  • R 2 is Ar—C s H 2s — and s is 0, i.e., R 2 is the group Ar and the group D thus is the group N(Ar).
  • the divalent alkanediyl group C s H 2s is a linear group.
  • a (C 1 -C 7 )-alkyl group representing R 2 is a (C 3 -C 7 )-alkyl group, in another embodiment a (C 3 -C 6 )-alkyl group.
  • a (C 3 -C 7 )-cycloalkyl group occurring in R 2 is a (C 3 -C 6 )-cycloalkyl group, in another embodiment a (C 5 -C 6 )-cycloalkyl group, in another embodiment a cyclopropyl group.
  • a group Ar occurring in R 2 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom, in another embodiment from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment from the series consisting of phenyl, thiophenyl, pyridinyl and pyrimidinyl, in another embodiment from the series consisting of phenyl and thiophenyl, in another embodiment from the series consisting of phenyl, pyridinyl and pyrimidinyl, in another embodiment from the series consisting of phenyl and pyridinyl, and in another embodiment a group Ar occurring in R 2 is phenyl, which groups all are optionally substituted as indicated with respect to the compounds of formula
  • a group Ar occurring in R 2 is optionally substituted by one, two or three identical or different substituents, in another embodiment it is optionally substituted by one or two identical or different substituents, in another embodiment it is optionally substituted by one substituent, in another embodiment it is substituted by one, two or three identical or different substituents, in another embodiment it is substituted by one or two identical or different substituents, and in another embodiment it is substituted by one substituent.
  • the substituents which are optionally present on a group Ar occurring in R 2 are chosen from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S(O) m — and NC—, in another embodiment from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-S(O) m —, in another embodiment from the series consisting of halogen, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkyl-S(O) m —, in another embodiment from the series consisting of halogen and (C 1 -C 6 )-alkyl, in another embodiment from the series consisting of halogen, in another embodiment from the series consisting of
  • a (C 1 -C 6 )-alkyl group occurring in R 2 is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment it is methyl.
  • Examples of groups Ar which can occur in R 2 are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-phenyl, 3,4-dichloro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3,
  • the group R 3 is chosen from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-O—, and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen and (C 1 -C 6 )-alkyl, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen and (C 1 -C 6 )-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and chlorine, in another embodiment R 3 is hydrogen, and in another embodiment R 3 is (C 1 -C 6 )-alkyl.
  • a (C 1 -C 6 )-alkyl group occurring in R 3 is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment it is methyl.
  • the group R 10 is chosen from the series consisting of R 11 —O— and R 12 —N(R 13 )—C(O)—O—, in another embodiment from the series consisting of R 12 —N(R 13 )—C(O)—O— and Het 2 -C(O)—O—, and in another embodiment R 10 is R 11 —O—.
  • the group Het 2 which can occur in the group R 2 , R 3 , R 4 or R 10 is a saturated 4-membered to 6-membered, in another embodiment a 5-membered or 6-membered, in another embodiment a 5-membered, monocyclic heterocycle which, besides the ring nitrogen via which Het 2 is bonded, optionally comprises one further ring heteroatom chosen from the series nitrogen, oxygen and sulfur.
  • the group Het 2 which can occur in the group R 2 , R 3 , R 4 or R 10 does not comprise a further ring heteroatom besides the ring nitrogen atom via which Het 2 is bonded.
  • the group Het 2 which can occur in the group R 2 , R 3 , R 4 or R 10 is selected from the series pyrrolidine, piperidine and morpholine.
  • the number of substituents which are optionally present on a group Het 2 which can occur in group R 2 , R 3 , R 4 or R 10 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het 2 is unsubstituted.
  • the substituents which are optionally present on a group Het 2 which can occur in the group R 2 , R 3 , R 4 or R 10 are chosen from the series consisting of fluorine, (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O—, in another embodiment from the series consisting of (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O—, in another embodiment from the series consisting of (C 1 -C 4 )-alkyl and HO— and (C 1 -C 4 )-alkyl-O—, in another embodiment they are (C 1 -C 4 )-alkyl substituents, and in another embodiment they are HO— substituents.
  • the group R 11 is chosen from the series consisting of hydrogen, R 14 , (C 3 -C 7 )-cycloalkyl and Het 3 , in another embodiment from the series consisting of hydrogen and R 14 , in another embodiment from the series consisting of hydrogen, R 14 and (C 3 -C 7 )-cycloalkyl, in another embodiment from the series consisting of (C 3 -C 7 )-cycloalkyl, Ar and Het 3 , in another embodiment from the series consisting of (C 3 -C 7 )-cycloalkyl and Het 3 , in another embodiment R 11 is hydrogen, in another embodiment R 11 is R 14 , and in another embodiment R 11 is Ar.
  • a group Ar representing R 11 is phenyl which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • a group Ar representing R 11 is optionally substituted by one, two or three identical or different substituents, in another embodiment it is optionally substituted by one or two identical or different substituents, in another embodiment it is optionally substituted by one substituent.
  • the substituents which are optionally present on a group Ar representing R 11 are chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—, in another embodiment from the series consisting of halogen and (C 1 -C 4 )-alkyl.
  • a (C 3 -C 7 )-cycloalkyl group representing R 11 is a (C 3 -C 6 )-cycloalkyl group.
  • a group Het 3 representing R 11 is a saturated 4-membered to 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, in another embodiment it comprises one ring heteroatom chosen from the series consisting of nitrogen and oxygen, in another embodiment one ring heteroatom chosen from the series consisting of oxygen and sulfur, and in another embodiment it comprises one oxygen atom as ring heteroatom, wherein the heterocycle is bonded via a ring carbon atom and is optionally substituted by one, two, three or four, in another embodiment by one or two, identical or different substituents chosen from the series consisting of fluorine, (C 1 -C 4 )-alkyl and oxo, in another embodiment from the series consisting of fluorine and (C 1 -C 4 )-alkyl.
  • the groups R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen and R 15 , in another embodiment from the series consisting of R 15 and Ar, and in another embodiment they are identical or different groups R 15 .
  • one of the groups R 12 and R 13 is chosen from the series consisting of R 15 and Ar, and the other is a group R 15 .
  • a group Ar representing R 12 or R 13 is phenyl which is optionally substituted by one or two, in another embodiment by one, identical or different substituents chosen from the series consisting of halogen and (C 1 -C 4 )-alkyl, and in another embodiment it is unsubstituted phenyl.
  • the (C 1 -C 10 )-alkyl group representing the group R 14 is a (C 1 -C 8 )-alkyl group, in another embodiment a (C 1 -C 7 )-alkyl group, in another embodiment a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a methyl group, in another embodiment a (C 4 -C 8 )-alkyl group, in another embodiment a (C 4 -C 7 )-alkyl group, in another embodiment a (C 5 -C 7 )-alkyl group, in another embodiment a C 6 -alkyl group, wherein all these alkyl groups are linear or branched as applies to alkyl groups in the compounds of the formula I in general, and are optionally substituted by one or more identical or different substituents
  • the number of optional substituents in an alkyl group representing R 14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one.
  • an alkyl group representing R 14 is unsubstituted, and in another embodiment it is substituted by one, two, three or four, in another embodiment by one, two or three, in another embodiment by one or two, in another embodiment by one substituent as indicated.
  • a (C 3 -C 7 )-cycloalkyl group occurring as a substituent on an alkyl group representing R 14 is a (C 3 -C 6 )-cycloalkyl group, in another embodiment it is a cyclopropyl group.
  • a group Ar occurring as a substituent on an alkyl group representing R 14 is phenyl or an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, and in another embodiment comprises one nitrogen atom as ring heteroatom and in the case of a 5-membered heterocycle one additional ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, and in another embodiment a group Ar occurring as a substituent in an alkyl group representing R 14 is chosen from phenyl, pyrazolyl, isoxazolyl and thiazolyl, wherein all these groups Ar are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the number of optional substituents on a group Ar occurring as a substituent in an alkyl group representing R 14 is one, two or three, in another embodiment one or two, in another embodiment one.
  • the substituents which are optionally present on a group Ar occurring as a substituent in an alkyl group representing R 14 are chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—, in another embodiment from the series consisting of halogen and (C 1 -C 4 )-alkyl, and in another embodiment they are (C 1 -C 4 )-alkyl groups.
  • a group Het 1 occurring as a substituent on an alkyl group representing R 14 is a saturated or unsaturated 4-membered to 6-membered heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • a group Het 1 occurring as a substituent on an alkyl group representing R 14 does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het 1 is bonded.
  • a group Het 1 occurring as a substituent on an alkyl group representing R 14 is saturated, in another embodiment it is unsaturated.
  • the number of substituents which are optionally present on a group Het 1 occurring as a substituent on an alkyl group representing R 14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one.
  • the substituents which are optionally present on a group Het 1 occurring as a substituent on an alkyl group representing R 14 are chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C 1 -C 4 )-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C 1 -C 4 )-alkyl and oxo, in another embodiment from the series consisting of (C 1 -C 4 )-alkyl and oxo, and in another embodiment they are oxo substituents.
  • the number of oxo substituents which are optionally present on a group Het 1 occurring as a substituent on an alkyl group representing R 14 is not greater than two, and in another embodiment it is not greater than
  • a group Het 1 occurring in the substituent Het 1 -C(O)— on an alkyl group representing R 14 is a 4-membered to 6-membered heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which is saturated or unsaturated and comprises a ring nitrogen atom via which Het 1 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, and which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • a group Het 1 occurring in the substituent Het 1 -C(O)— on an alkyl group representing R 14 does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het 1 is bonded.
  • a group Het 1 occurring in the substituent Het 1 -C(O)— on an alkyl group representing R 14 is saturated or comprises one double bond within the ring, and in another embodiment it is saturated.
  • the number of substituents which are optionally present on a group Het 1 occurring in the substituent Het 1 -C(O)— on an alkyl group representing R 14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one.
  • the substituents which are optionally present on a group Het 1 occurring in the substituent Het 1 -C(O)— on an alkyl group representing R 14 are chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C 1 -C 4 )-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C 1 -C 4 )-alkyl and oxo, in another embodiment from (C 1 -C 4 )-alkyl and oxo, in another embodiment they are oxo substituents, and in another embodiment they are (C 1 -C 4 )-alkyl substituents.
  • the number of oxo substituents which are optionally present on a group Het 1 occurring in the substituent Het 1 -C(O)— on an alkyl group representing R 14 is not greater than two, and in another embodiment it is not greater than one, and in another embodiment no oxo substituents are present on such a group Het 1 .
  • a group Het 3 occurring as a substituent on an alkyl group representing R 14 is a saturated 4-membered to 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, and in another embodiment comprises one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom and is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the ring heteroatoms in a group Het 3 occurring as a substituent on an alkyl group representing R 14 are chosen from the series consisting of nitrogen and oxygen, in another embodiment from the series consisting of oxygen and sulfur, in another embodiment they are nitrogen atoms, and in another embodiment they are oxygen atoms.
  • the number of substituents which are optionally present on a group Het 3 occurring as a substituent on an alkyl group representing R 14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one.
  • the substituents which are optionally present on a group Het 3 occurring as a substituent on an alkyl group representing R 14 are chosen from the series consisting of fluorine and (C 1 -C 4 )-alkyl, in another embodiment from the series consisting of (C 1 -C 4 )-alkyl and oxo, in another embodiment they are (C 1 -C 4 )-alkyl substituents, and in another embodiment they are oxo substituents.
  • the number of oxo substituents which are optionally present on a group Het 3 occurring as a substituent on an alkyl group representing R 14 is not greater than two, and in another embodiment it is not greater than one.
  • the substituents which are optionally present on an alkyl group representing R 14 are chosen from the series consisting of halogen, HO—, R 16 —O—, oxo, (C 3 -C 7 )-cycloalkyl, Ar, Het 1 , Het 3 , H 2 N—C(O)—, (C 1 -C 4 )-alkyl-NH—C(O)—, di((C 1 -C 4 )-alkyl)N—C(O)— and Het 1 -C(O)—, in another embodiment from the series consisting of halogen, HO—, R 16 —O—, oxo, (C 3 -C 7 )-cycloalkyl, Het 1 , Het 3 , H 2 N—C(O)—, (C 1 -C 4 )-alkyl-NH—C(O)—, di((C 1 -C 4 )-alkyl)N—C(O)—
  • the number of oxo substituents which are optionally present on an alkyl group representing R 14 is not greater than two, and in another embodiment it is not greater than one.
  • halogen atoms occurring as substituents on an alkyl group representing R 14 are chosen from the series consisting of fluorine and chlorine atoms, and in another embodiment they are fluorine atoms and, besides being substituted by an other substituents, in this latter embodiment an alkyl group representing R 14 is thus optionally substituted by fluorine substituents as applies to alkyl groups in the compounds of the formula I in general.
  • Examples of groups which can represent R 14 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, benzyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 2-hydroxy-butyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-butyl, 2-hydroxy-3-methyl-butyl, 2-hydroxy-2,3-dimethyl-butyl, 2-hydroxy-3,3-dimethyl-butyl, 2-ethyl-2-hydroxy-butyl, 2-hydroxy-2,3,3-trimethyl-butyl, 2-ethyl-2-hydroxy-3-methyl-butyl, 2-ethyl-2-hydroxy-3,3-dimethyl-butyl, 2-cyclopropyl-2-hydroxy-ethyl, 2-cyclopropyl-2-hydroxy-propyl, 2-cyclopropyl-2-hydroxy-butyl, 2-cyclopropyl-2-hydroxy-propyl, 2-cyclo
  • the compound of the formula I can be present with respect to this carbon atom in any of it stereoisomeric forms, i.e. in R configuration or in S configuration, or in the form of a mixture of the stereoisomeric forms in any ratio, for example as a mixture of the two stereoisomeric forms in a molar ratio of 1:1, as applies to all chiral carbon atoms in the compounds of the formula I.
  • the compound of the formula I has at a chiral carbon atom in R 14 pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater.
  • the (C 1 -C 6 )-alkyl group representing the group R 15 is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a methyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the number of optional substituents in an alkyl group representing R 15 is one or two, in another embodiment one.
  • the alkyl group representing R 15 is unsubstituted.
  • the substituents which are optionally present on an alkyl group representing R 15 are chosen from the series consisting of HO— and (C 1 -C 4 )-alkyl-O—.
  • the (C 1 -C 6 )-alkyl group representing the group R 16 is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 2 -C 3 )-alkyl group, in another embodiment an ethyl group, in another embodiment a methyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the number of optional substituents in an alkyl group representing R 16 is one or two, in another embodiment one.
  • an alkyl group representing R 14 is unsubstituted, in another embodiment it is substituted by one or two identical or different substituents, in another embodiment it is substituted by one substituent.
  • the substituents which are optionally present on an alkyl group representing R 15 are chosen from the series consisting of HO— and (C 1 -C 4 )-alkyl-O—, in another embodiment they are HO— substituents, in another embodiment they are (C 1 -C 4 )-alkyl-O— substituents, and in another embodiment they are (C 1 -C 2 )-alkyl-O— substituents.
  • the group R 30 is chosen from the series consisting of R 31 , (C 3 -C 7 )-cycloalkyl and Het 3 -C u H 2u —, in another embodiment from the series consisting of (C 3 -C 7 )-cycloalkyl, R 32 —C u H 2u — and Het 3 -C u H 2u , in another embodiment from the series consisting of R 32 —C u H 2u — and Het 3 -C u H 2u —, in another embodiment R 30 is R 32 —C u H 2u —, and in another embodiment R 30 is R 31 .
  • u is an integer chosen from the series consisting of 0, 1 and 2, in another embodiment from the series consisting of 0 and 1, in another embodiment from the series consisting of 1 and 2, in another embodiment u is 0, and in another embodiment u is 1.
  • R 30 is R 32 —C u H 2u — and u is 0, i.e., in this embodiment R 30 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the divalent alkanediyl group C u H 2u is a linear group.
  • the (C 3 -C 7 )-cycloalkyl group representing R 30 is a (C 3 -C 6 )-cycloalkyl group, in another embodiment a (C 5 -C 6 )-cycloalkyl group, in another embodiment a cyclopropyl group.
  • a group Het 3 occurring in R 30 is a saturated 4-membered to 6-membered monocyclic heterocycle, in another embodiment a saturated 5-membered or 6-membered heterocycle, in another embodiment a saturated 6-membered heterocycle, which comprises one or two identical or different ring heteroatoms, and in another embodiment comprises one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom and is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the ring heteroatoms in a group Het 3 occurring in R 30 are chosen from the series consisting of nitrogen and oxygen, in another embodiment from the series consisting of oxygen and sulfur, in another embodiment they are nitrogen atoms, and in another embodiment they are oxygen atoms.
  • the number of substituents which are optionally present on a group Het 3 occurring in R 30 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment a group Het 3 occurring in R 30 is unsubstituted.
  • the substituents which are optionally present on a group Het 3 occurring in R 30 are chosen from the series consisting of fluorine and (C 1 -C 4 )-alkyl, in another embodiment they are (C 1 -C 4 )-alkyl substituents.
  • the (C 1 -C 10 )-alkyl group representing R 31 is a (C 1 -C 8 )-alkyl group, in another embodiment a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a methyl group, in another embodiment a (C 4 -C 8 )-alkyl group, in another embodiment a (C 5 -C 8 )-alkyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the number of optional substituents in an alkyl group representing R 31 is one, two or three, in another embodiment one or two, in another embodiment one.
  • an alkyl group representing R 31 is unsubstituted, and in another embodiment it is substituted by one, two or three, in another embodiment by one or two, in another embodiment by one substituent as indicated.
  • the optional substituents on an alkyl group representing R 31 are chosen from the series consisting of halogen, (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C 3 -C 7 )-cycloalkyl and (C 1 -C 6 )-alkyl-O—, in another embodiment from the series consisting of halogen and (C 3 -C 7 )-cycloalkyl, and in another embodiment they are (C 3 -C 7 )-cycloalkyl substituents.
  • halogen atoms occurring as substituents on an alkyl group representing R 31 are chosen from the series consisting of fluorine and chlorine atoms, and in another embodiment they are fluorine atoms and, besides being substituted by an other substituents, in this latter embodiment an alkyl group representing R 31 is thus optionally substituted by fluorine substituents as applies to alkyl groups in the compounds of the formula I in general.
  • a (C 3 -C 7 )-cycloalkyl group occurring as a substituent on an alkyl group representing R 30 is a (C 3 -C 6 )-cycloalkyl group, in another embodiment a (C 5 -C 6 )-cycloalkyl group, in another embodiment a cyclopropyl group.
  • the group R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, in another embodiment from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the ring heteroatoms in an aromatic heterocycle representing R 32 are chosen from the series consisting of nitrogen and sulfur, in another embodiment they are nitrogen atoms.
  • R 32 is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle as defined, in another embodiment R 32 is a 6-membered monocyclic heterocycle as defined, in another embodiment R 32 is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment R 32 is phenyl, and in another embodiment R 32 is pyridinyl, all of which are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the number of substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R 32 is one, two, three or four, in another embodiment one, two or three
  • the substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R 32 , in particular on a phenyl group are chosen from the series the series consisting of from halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , (C 1 -C 6 )-alkyl-O—, R 33 —O—, R 33 —(C 1 -C 4 )-alkyl-O—, —O—CH 2 —O—, —O—CF 2 —O—, (C 1 -C 6 )-alkyl-S(O) m —, H 2 N—S(O) 2 —, (C 1 -C 4 )-alkyl-NH—S(O) 2 —, di((C 1 -C 4 )-alkyl)N—S(O) 2 —, (C 1 -C 6 )-alkyl
  • R 33 , R 33 —O—, R 33 —(C 1 -C 4 )-alkyl-O—, —O—CH 2 —O—, —O—CF 2 —O—, Het 1 and Ar—C(O)—NH— are present on a phenyl group and an aromatic heterocycle representing R 32 , not more than two such substituents, in another embodiment not more than one such substituent, are present, either without any other substituents or together with any other substituents.
  • a (C 1 -C 6 )-alkyl group occurring in a substituent on a phenyl group and an aromatic heterocycle representing R 32 is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a methyl group.
  • a (C 3 -C 7 )-cycloalkyl group occurring as a substituent on a phenyl group and an aromatic heterocycle representing R 32 is a (C 3 -C 6 )-cycloalkyl group, in another embodiment a (C 3 -C 5 )-cycloalkyl group, in another embodiment a (C 3 -C 4 )-cycloalkyl group, in another embodiment it is a cyclopropyl group.
  • a group Ar occurring in a substituent on a phenyl group and an aromatic heterocycle representing R 32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, chosen from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom, and in another embodiment it is a phenyl group, which groups all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the number of optional substituents on a group Ar occurring in a substituent on a phenyl group and an aromatic heterocycle representing R 32 is one or two, in another embodiment one, and the optional substituents are chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl-O—, (C 1 -C 4 )-alkyl-S(O) m — and NC—, in another embodiment from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—, in another embodiment from the series consisting of halogen and (C 1 -C 4 )-alkyl, and in another embodiment such a group Ar is unsubstituted.
  • a group Het 1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R 32 is a saturated or unsaturated 4-membered to 6-membered monocyclic heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which comprises a ring nitrogen atom via which Het 1 is bonded and optionally one or two further ring heteroatoms, in another embodiment one further ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • a group Het 1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R 32 does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het 1 is bonded.
  • a group Het 1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R 32 is saturated, in another embodiment it is unsaturated.
  • the number of substituents which are optionally present on a group Het 1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R 32 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het 1 is unsubstituted.
  • the substituents which are optionally present on a group Het 1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R 32 are chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C 1 -C 4 )-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C 1 -C 4 )-alkyl and oxo, and in another embodiment they are (C 1 -C 4 )-alkyl substituents.
  • R 32 from any one or more of which R 32 is chosen in one embodiment of the invention are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-phenyl, 3,4-dichloro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl, 2-methyl-
  • the group R 33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which is chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the ring heteroatoms in an aromatic heterocycle representing R 33 are chosen from the series consisting of nitrogen and sulfur, in another embodiment they are nitrogen atoms.
  • R 33 is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle as defined, in another embodiment from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment R 33 is a 6-membered monocyclic heterocycle as defined, in another embodiment it is an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment R 33 is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment R 33 is phenyl, and in another embodiment R 33 is pyridinyl, all of which are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on a phenyl and an
  • the substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R 33 are chosen from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 6 )-alkyl-O—, H 2 N—S(O) 2 —, di((C 1 -C 4 )-alkyl)N—S(O) 2 — and NC—, in another embodiment from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 6 )-alkyl-O—, H 2 N—S(O) 2 —, di((C 1 -C 4 )-alkyl)N—S(O) 2 — and NC—, in another embodiment from the series consisting of halogen, (C 1 -C 6
  • a (C 1 -C 6 )-alkyl group occurring in a substituent on a phenyl group and an aromatic heterocycle representing R 33 is a (C 1 -C 4 )-alkyl group, in another embodiment a (C 1 -C 3 )-alkyl group, in another embodiment a (C 1 -C 2 )-alkyl group, in another embodiment a methyl group.
  • a (C 3 -C 7 )-cycloalkyl group occurring as a substituent on a phenyl group and an aromatic heterocycle representing R 32 is a (C 3 -C 6 )-cycloalkyl group, in another embodiment a (C 3 -C 6 )-cycloalkyl group, in another embodiment a (C 3 -C 4 )-cycloalkyl group, in another embodiment it is a cyclopropyl group.
  • the group R 40 is chosen from the series consisting of hydrogen and (C 1 -C 2 )-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R 40 is hydrogen.
  • R 30 and R 40 are different and the carbon atom carrying R 30 and R 40 thus is chiral
  • the compound of the formula I has at this carbon atom pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater.
  • R 30 is R 32 —C u H 2u — and u is 0, i.e.
  • R 30 is phenyl or an aromatic heterocycle as defined, R 40 is hydrogen and R 50 is hydrogen, in one embodiment of the invention the compound of the formula I has at the carbon atom carrying R 30 and R 40 pure S configuration, or essentially pure S configuration, for example with a molar ratio of S configuration to R configuration of 99:1 or greater.
  • R 30 and R 40 together are a divalent group (CH 2 ) x
  • the two groups R 30 and R 40 together with the carbon atom carrying them form a cycloalkane ring chosen from cyclopropane, cyclobutane, cyclopentane and cyclohexane, which carries the moieties —C(O)—NH and —C(R 50 )(R 60 )-G depicted in formula I on the same ring carbon atom.
  • the number of (C 1 -C 4 )-alkyl substituents which are optionally present on the group (CH 2 ) x is one, two, three or four, in another embodiment one or two, and in another embodiment no alkyl substituents are present on the group (CH 2 ) x .
  • a (C 1 -C 4 )-alkyl group occurring as a substituent on the group (CH 2 ) x is a methyl group.
  • the integer x is chosen from the series consisting of 2, 4 and 5, in another embodiment from 4 and 5, in another embodiment x is 2, and in another embodiment x is 4.
  • R 30 and R 40 together cannot be (CH 2 ) x , and in this embodiment R 30 and R 40 thus only have their other meanings as defined.
  • the group R 50 is chosen from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and HO—, in another embodiment from the series consisting of hydrogen and (C 1 -C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (C 1 -C 2 )-alkyl, in another embodiment from the series consisting of hydrogen and methyl, in another embodiment from the series consisting of hydrogen and HO—, and in another embodiment R 50 is hydrogen.
  • the group R 60 is chosen from the series consisting of hydrogen and (C 1 -C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (C 1 -C 3 )-alkyl, in another embodiment from the series consisting of hydrogen and (C 1 -C 2 )-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R 60 is hydrogen.
  • R 50 and R 60 both are hydrogen.
  • the compound of the formula I has at this carbon atom pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater.
  • R 50 and R 60 together are a divalent group (CH 2 ) y
  • the two groups R 50 and R 60 together with the carbon atom carrying them form a cycloalkane ring chosen from cyclopropane, cyclobutane, cyclopentane and cyclohexane, which carries the moieties and G depicted in formula I on the same ring carbon atom.
  • the number of (C 1 -C 4 )-alkyl substituents which are optionally present on the group (CH 2 ) y is one, two, three or four, in another embodiment one or two, and in another embodiment no alkyl substituents are present on the group (CH 2 ) y .
  • a (C 1 -C 4 )-alkyl group occurring as a substituent on the group (CH 2 ) y is a methyl group.
  • the integer y is chosen from the series consisting of 2, 4 and 5, in another embodiment from 4 and 5, in another embodiment y is 2, and in another embodiment y is 4.
  • R 50 and R 60 together cannot be (CH 2 ) y , and in this embodiment R 50 and R 60 thus only have their other meanings as defined.
  • R 50 and R 60 together cannot be (CH 2 ) y if simultaneously R 30 and R 40 together are (CH 2 ) x .
  • the group R 71 is chosen from the series consisting of hydrogen and (C 1 -C 6 )-alkyl, in another embodiment from the series consisting of hydrogen and (C 1 -C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (C 1 -C 3 )-alkyl, in another embodiment from the series consisting of hydrogen and (C 1 -C 2 )-alkyl, in another embodiment R 71 is hydrogen, in another embodiment R 71 is (C 1 -C 6 )-alkyl, in another embodiment R 71 is (C 1 -C 4 )-alkyl, in another embodiment R 71 is (C 1 -C 3 )-alkyl, and in another embodiment R 71 is (C 1 -C 2 )-alkyl, wherein all these alkyl groups are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • the number of substituents which are optionally present on an alkyl group representing R 71 is one or two, in another embodiment it is one, in another embodiment an alkyl group representing R 71 is unsubstituted.
  • substituents which are optionally present on an alkyl group representing R 71 are (C 1 -C 6 )-alkyl-O-substituents, in another embodiment (C 1 -C 4 )-alkyl-O— substituents, in another embodiment (C 1 -C 3 )-alkyl-O— substituents, in another embodiment (C 1 -C 6 )-alkyl-C(O)—O— substituents, in another embodiment (C 1 -C 4 )-alkyl-C(O)—O— substituents, in another embodiment (C 1 -C 3 )-alkyl-C(O)—O— substituents.
  • the group R 72 is chosen from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl —CH 2 —(CH 2 ) b —(C 3 -C 6 )-cycloalkyl and —(CH 2 ) b -Het 4 , where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-C(O)—O—, NC—, N((C 1 -C 4 )-alkyl) 2 and b is 0, 1 or 2 and the group R 73 is chosen from the series consisting hydrogen, (C 1 -C 6 )-alkyl.
  • the groups R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O—.
  • the group R 72 is chosen from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, Het 4 and —CH 2 -Het 4 , where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-C(O)—O—, NC—, N((C 1 -C 4 )-alkyl) 2 and the group R 73 is chosen from the series consisting hydrogen, (C 1 -C 6 )-alkyl.
  • the groups R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 5-membered to 6-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O—.
  • the group R 72 is chosen from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl and —CH 2 -Het 4 , where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-C(O)—O—, NC—, N((C 1 -C 4 )-alkyl) 2 and the group R 73 is chosen from the series consisting hydrogen and (C 1 -C 6 )-alkyl.
  • the groups R 72 and R 73 together with the nitrogen atom to which they are bonded form a saturated 5-membered to 6-membered monocyclic heterocycle, which contain no further ring heteroatoms, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO— and (C 1 -C 4 )-alkyl-O—.
  • the group R 72 is chosen from the series consisting of hydrogen, 2,2-dimethyl-butane-3yl, 2,2-dimethyl-propane-3yl, pentan-3yl, propane-2yl, 2-methyl-propane-2yl, butane-1yl, butane-2yl, 2-methyl-butane-3yl, 2-methyl-butane-2-yl, —CH 2 CHF 2 , —CHCF 3 , CH 2 CN, —CH 2 CH 2 OCH 3 , —CH(CH 2 OH)CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 —CH 2 OH, CH(C 2 H 5 )CH 2 OCH 3 , CH 2 CH 2 CH 2 N(CH 3 ) 2 , cyclopropane, cyclobutane, cyclopentane, cyclohexane and —CH 2 -Het 4 and the group R 73 is hydrogen.
  • group R 72 is chosen from the series consisting of hydrogen, (C 1 -C 6 )-alkyl, where alkyl is substituted by one or more times by HO— and the group R 73 is hydrogen.
  • the groups R 72 and R 73 are independently of each other chosen from the series consisting of hydrogen and (C 1 -C 2 )-alkyl, in another embodiment from the series consisting of hydrogen and methyl.
  • one of the groups R 72 and R 73 is hydrogen and the other is chosen from the series consisting of hydrogen and (C 1 -C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (C 1 -C 2 )-alkyl, in another embodiment from the series consisting of hydrogen an methyl, and in another embodiment both groups R 72 and R 73 are hydrogen.
  • the group Het 4 is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O—, oxo and NC—;
  • the group Het 4 independently of each other group Het 4 , is a saturated or unsaturated 5-membered to 6-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )
  • the group Het 4 is a unsaturated 5-membered to 6-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 4 )-alkyl, HO—, (C 1 -C 4 )-alkyl-O— and NC—;
  • the group Het 4 independently of each other group Het 4 , is selected from 1,2-oxadiazolyl, tetrazlolyl, pyrazolyl, furanyl, pyridinyl, pyriminyl, which is optionally substituted by methyl.
  • a group Ar in any occurrence in the compounds of the formula I, independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which is chosen from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom, in another embodiment Ar is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment Ar is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and thiophenyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment a group Ar is phenyl, and in another embodiment a group Ar is pyridinyl, where
  • the number of substituents which are optionally present on a group Ar, independently of each other group Ar is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment a group Ar is unsubstituted.
  • substituents from the series consisting of —CH ⁇ CH—CH ⁇ CH—, —O—CH 2 —CH 2 —O—, —N((C 1 -C 3 )-alkyl)-CH ⁇ CH—, —O—CH 2 —O— and —O—CF 2 —O— are present on a group Ar which is phenyl, not more than two such substituents, in another embodiment not more than one such substituent, are present, either without any other substituents or together with any other substituents.
  • the substituents which are optionally present on a group Ar, independently of each other group Ar are chosen from the series consisting of halogen, (C 1 -C 6 )-alkyl, HO—(C 1 -C 6 )-alkyl, Het4, —(CH 2 ) x -phenyl, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-(CH 2 ) x —O—, —CF 3 , —CO—(C 1 -C 6 )-alkyl, —NR 12 R 13 , Het 2 , —CO—NR 12 R 13 , CO-Het 2 , (C 1 -C 6 )-alkyl-S(O) m —, H 2 N—S(O) 2 — and NC—; in another embodiment from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6
  • a subject of the invention are all compounds of the formula I wherein any one or more structural elements such as groups, substituents and numbers are defined as in any of the specified embodiments or definitions of the elements or have one or more of the specific meanings which are mentioned herein as examples of elements, wherein all combinations of one or more specified embodiments and/or definitions and/or specific meanings of the elements are a subject of the present invention. Also with respect to all such compounds of the formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratios, and their physiologically acceptable salts, and the physiologically acceptable solvates of any of them, are a subject of the present invention.
  • G is chosen from the series consisting of R 71 —O—C(O)— and R 72 —N(R 73 )—C(O)—;
  • R 30 is R 32 —C u H 2u —, wherein u is an integer chosen from the series consisting of 0 and 1;
  • R 32 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , HO—, (C 1 -C 6 )-alkyl-O—, R 33 —O—, R 33 —(C 1 -C 4 )-alkyl-O—, —O—CH 2 —O—, —O—CF 2 —O—, (C 1 -C 6 )-alkyl-S(O) m —, di((C 1 -C 4 )-alkyl)N—S(O) 2 —, H 2 N—, di((C 1 -C 6 )-alkyl
  • R 33 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, HO—, (C 1 -C 6 )-alkyl-O —, (C 1 -C 6 )-alkyl-S(O) m —, H 2 N—S(O) 2 —, di((C 1 -C 4 )-alkyl)N—S(O) 2 — and NC—; R 40 is hydrogen.
  • G is R 71 —O—C(O)—
  • R 30 is R 32 —C u H 2u —, wherein u is 0;
  • R 32 is chosen from the series consisting of phenyl, wherein the phenyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, R 33 , HO—, (C 1 -C 6 )-alkyl-O—, R 33 —O—, R 33 —(C 1 -C 4 )-alkyl-O—, —O—CH 2 —O—, —O—CF 2 —O—, (C 1 -C 6 )-alkyl-S(O) m —, di((C 1 -C 4 )-alkyl)N—S(O) 2 —, H 2 N—, di((C 1 -C 6 )-alkyl)N—, Het
  • formula I is selected from the series of subformulae I-1 to I-7
  • R 2 is Ar—C s H 2s —, wherein s is an integer chosen from the series consisting of 0;
  • R 3 is chosen from the series consisting of hydrogen, halogen, R 11 —O—, HO—, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkyl-O—; preferred HO— and (C 1 -C 6 )-alkyl;
  • R 4 is hydrogen;
  • R 10 is hydrogen;
  • R 1 is hydrogen
  • R 3 is chosen from the series consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-S(O) m —, Phenyl C s H 2s —(O) t —, Het 4 -(O) t —, —NR 12 R 13 , Het 2 , R 11 —O—, R 12 —N(R 13 )—C(O)—O— and Het 2 -C(O)—O— and NC—, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1;
  • R 4 is hydrogen
  • R 10 is chosen from the series consisting hydrogen, halogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S(O) m —, HO—, —NR 12 R 13 , Het 2 , phenyl-C s H 2s —(O) t —, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1;
  • a subject of the invention also is a compound of the formula I which is chosen from any of the specific compounds of the formula I which are disclosed herein, or is any one of the specific compounds of the formula I which are disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a specific salt, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein the compound of the formula I is a subject of the invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio.
  • a subject of the invention is a compound of the formula I which is chosen from
  • a subject of the invention is a compound of the formula I which is chosen from
  • Another subject of the present invention are processes for the preparation of the compounds of the formula I which are outlined below and by which the compounds are obtainable.
  • the preparation of the compounds of the formula I can be carried out by reacting a compound of the formula II with a compound of the formula III with formation of an amide bond.
  • Various synthetic methods for the formation of the amide bond are described in C. A. G. N. Montalbetti et al., Tetrahedron 61 (2005), 10827-10852, for example.
  • the formation of the amide bond between the carboxylic acid and the ⁇ -amino-acid can be done by the use of coupling agents well known to a person skilled in the art and described for example in Tetrahedron (2005), 61(46), 10827-10852.
  • a carboxylic acid a carboxylic acid chloride and instead of the free ⁇ -amino acid a ⁇ -amino acid ester, especially methyl- or ethylester, may be used.
  • ⁇ -amino-acids used within this work are either commercially available or prepared by methods described for example in JACS 1935, 1279 or by Rhodionow in Chem. Abstr. 1953, 1051.
  • Rhodionow scheme is depicted below:
  • Enantiopure ⁇ -amino acids can either be obtained commercially or prepared from the racemic material by procedures described in Bioscience, Biotechnology and Biochemistry, 2006, 1941.
  • 0.25 mmol of the carboxylic acid is weighed into a reaction vial, 1.25 mmol N-ethyl morpholine in 1 ml DMF is added, followed by 0.245 mmol TOTU in 0.5 ml DMF. The mixture is allowed to react for 30 min at RT. 0.275 mmol of the amino acid suspended in 0.5 ml DMF is added, the vial is closed with a screw cap and shaken over night at RT. 0.2 ml TFA is added, the solution is filtered through syringe filters and directly submitted to prep HPLC.
  • Another general procedure consists of the synthesis of amino acid derivatives with a functional group suitable for a subsequent Suzuki reaction as shown below.
  • Step 1 Esterification of ⁇ -amino acids
  • Step 2 Coupling of products from 1 to heterocyclic carboxylic acids substituted with chlorine or bromine atoms:
  • Step 3 Hydrolysis of products from step 2:
  • the groups A, D, E, L, G, R 10 , R 30 , R 40 , R 50 and R 60 in the compounds of the formulae II and III are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group which is later converted into the final group.
  • the group J in the compounds of the formula II can be HO— (hydroxy), i.e.
  • the compound of the formula II can thus be a carboxylic acid, or another group which can be replaced by the group NH in the compound of the formula III in a substitution reaction, for example an aryloxy group such as optionally substituted phenoxy or an alkyloxy group such as a (C 1 -C 4 )-alkyl-O— group, for example a (C 1 -C 3 )-alkyl-O— group like methoxy or ethoxy, or halogen, for example chlorine or bromine, and the compound of the formula II can thus be a reactive ester like an aryl ester or alkyl ester, for example a methyl ester or ethyl ester, or an acid halide, for example an acid chloride or acid bromide, of the respective carboxylic acid.
  • an aryloxy group such as optionally substituted phenoxy or an alkyloxy group such as a (C 1 -C 4 )-alkyl-O— group, for example a (
  • the compounds of the formulae II and III can also be employed, and the compounds of the formula I obtained, in the form of a salt, for example an acid addition salt such as an hydrohalide, for example a hydrochloride, of the compound of the formula III and/or an alkaline metal salt, for example a sodium salt, of a compound of the formula II in which J is HO—.
  • a salt for example an acid addition salt such as an hydrohalide, for example a hydrochloride
  • an alkaline metal salt for example a sodium salt
  • the carboxylic acid group HO—C(O)— is generally activated in situ by means of a customary amide coupling reagent or converted into a reactive carboxylic acid derivative which can be prepared in situ or isolated.
  • the compound of the formula II in which J is HO— can be converted into an acid halide, such as the compound of the formula II in which J is chlorine or bromine, by treatment with thionyl chloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride, or treated with an alkyl chloroformate like ethyl chloroformate or isobutyl chloroformate to give a mixed anhydride.
  • an acid halide such as the compound of the formula II in which J is chlorine or bromine
  • the acid is treated with oxalyl chloride in the presence of a catalytic amount of an amide such as N,N-dimethylformamide in an inert solvent such as a hydrocarbon or chlorinated hydrocarbon or an ether, at temperatures from about 0° C. to about 60° C., for example at room temperature.
  • an amide such as N,N-dimethylformamide
  • an inert solvent such as a hydrocarbon or chlorinated hydrocarbon or an ether
  • Customary amide coupling reagents which can be employed, are propanephosphonic anhydride, N,N′-carbonyldiazoles like N,N′-carbonyldiimidazole (CDI), carbodiimides like 1,3-diisopropylcarbodiimide (DIC), 1,3-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbodiimides together with additives like 1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), uronium-based coupling reagents like O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-te
  • reaction conditions for the preparation of the compounds of the formula I from compounds of the formulae II and III depend on the particulars of the specific case, for example the meaning of the group J or the employed coupling reagent, and are familiar to a skilled person in view of the general knowledge in the art.
  • reaction is carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform or dichloroethane, an ether like tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME), or a mixture of solvents, at elevated temperatures, for example at temperatures from about 40° C.
  • an inert solvent for example a hydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform or dichloroethane, an ether like tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, dibutyl ether, diisopropyl ether or dimeth
  • reaction is likewise carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon or ether like the aforementioned ones, an ester like ethyl acetate or butyl acetate, a nitrile like acetonitrile, or water, or a mixture of solvents including a mixture of water and an organic solvent which is miscible or immiscible with water, at temperatures from about ⁇ 10° C.
  • an inert solvent for example a hydrocarbon or chlorinated hydrocarbon or ether like the aforementioned ones, an ester like ethyl acetate or butyl acetate, a nitrile like acetonitrile, or water, or a mixture of solvents including a mixture of water and an organic solvent which is miscible or immiscible with water, at temperatures from about ⁇ 10° C.
  • reaction of a compound of the formula II in which J is halogen with a compound of the formula III is carried out in the presence of a base such as a tertiary amine, like triethylamine, N-ethyl-diisopropylamine (EDIA), N-methylmorpholine, N-ethylmorpholine or pyridine, or an inorganic base such as an alkaline metal hydroxide, carbonate or hydrogencarbonate, like sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate.
  • a base such as a tertiary amine, like triethylamine, N-ethyl-diisopropylamine (EDIA), N-methylmorpholine, N-ethylmorpholine or pyridine
  • an inorganic base such as an alkaline metal hydroxide, carbonate or hydrogencarbonate, like sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate.
  • reaction is generally carried out under anhydrous conditions in an inert aprotic solvent, for example an ether like THF, dioxane or DME, an amide like N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), at temperatures from about ⁇ 10° C. to about 40° C., in particular at temperatures from about 0° C.
  • an inert aprotic solvent for example an ether like THF, dioxane or DME, an amide like N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP)
  • a base such as a tertiary amine, like triethylamine, EDIA, N-methylmorpholine or N-ethylmorpholine.
  • a base such as a tertiary amine, like triethylamine, EDIA, N-methylmorpholine or N-ethylmorpholine.
  • protective groups which may be mentioned, are benzyl protective groups which may occur in the form of benzyl ethers of hydroxy groups and benzyl esters of carboxylic acid groups from which the benzyl group can be removed by catalytic hydrogenation in the presence of a palladium catalyst, tert-butyl protective groups which may occur in the form of tert-butyl esters of carboxylic acid groups from which the tert-butyl group can be removed by treatment with trifluoroacetic acid, acyl protective groups which may be used to protect hydroxy groups and amino groups in the form of esters and amides and which can be cleaved by acidic or basic hydrolysis, and alkyloxycarbonyl protective groups which may occur in the form of tert-butoxycarbonyl derivatives of amino groups which can be clea
  • carboxylic acid groups for example the carboxylic acid group present in the compound of the formula III in case G is a carboxylic acid group in the desired compound of the formula I, can also be avoided by employing them in the reaction with the compounds of the formula II in the form of other esters, for example in the form of alkyl esters like the methyl or ethyl ester which can be cleaved by hydrolysis, for example by means of an alkaline metal hydroxide like sodium hydroxide or lithium hydroxide.
  • the cyano group (NC—, N ⁇ C—) may be mentioned which can be converted into a carboxylic acid group, a carboxylic acid ester group and a carboxamide group under hydrolytic conditions or into a aminomethyl group by reduction, and the nitro group which can be converted into an amino group by reduction, for example by catalytic hydrogenation or by reduction with sodium dithionite, for example.
  • a further example of a precursor group is an oxo group, which may initially be present in the course of the synthesis of compounds of the formula I containing a hydroxy group, and which can be reduced, for example with a complex hydride such as sodium borohydride, or reacted with an organometallic compound, for example a Grignard compound. If any protective groups or precursor groups are present in the compounds of the formulae II and III and the direct product of the reaction is not yet the desired final compound, the removal of the protective group or conversion into the desired compound can in general also be carried out in situ.
  • the starting compounds for the synthesis of the compounds of the formula I can generally be prepared according to procedures described in the literature or analogously to such procedures, or are commercially available.
  • ⁇ -amino acids and derivatives of the formula III are commercially available or can be synthesized by well-known standard methods, or analogously to such methods, from readily available starting compounds.
  • R 50 and R 60 can carbonyl compounds of the formula R 30 —C(O)—R 40 , in particular aldehydes of the formula R 32 —C(O)—H, be reacted with malonic acid mono-ethyl ester and ammonia in the presence of a base such as an alkaline metal hydroxide like potassium hydroxide in a solvent such as an alcohol like ethanol, as described in V. M.
  • Enantiomerically pure such compounds of the formula III can be obtained from the racemic compounds by crystallization of a salt with an optically active acid, such as tartaric acid, by stereoselective enzymatic or microbial degradation, for example as described in the mentioned article by M. K. Tse et al., or in J. Mano et al., Bioscience, Biotechnology and Biochemistry 70 (2006), 1941-1946.
  • the respective 3-substituted acrylic acid which can be obtained from the corresponding aldehyde, is converted into the acid chloride, for example with oxalyl chloride, and the acid chloride converted with an alcohol into an ester, for example into the tert-butyl ester using tert-butanol, and the amino group is then introduced by reaction with the lithium salt of an optically active amine, for example the lithium salt of (R)-(+)—N-benzyl-N-(1-phenylethyl)amine, and in the obtained 3-substituted tert-butyl 3-(N-benzyl-N-(1-phenylethyl)amino)propionate the benzyl group and the phenylethyl group is cleaved off by means of catalytic hydrogenation (cf. S. G.
  • the groups A, D, E, L, G, R 30 , R 40 , R 50 and R 60 in the compounds of the formulae Ia, Ib and IIc are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group which is later converted into the final group.
  • the group J in the compounds of the formula IIc is defined as in the compounds of the formula II.
  • the group R 10a in the compounds of the formula Ib is defined as in the compounds of the formulae IIb and VIII.
  • a hydroxy group including a hydroxy group representing R 10 in a compound of the formula I, can be etherified, as outlined above, for example by alkylation with a halogen compound, for example a bromide or iodide, in the presence of a base such an alkali metal carbonate like potassium carbonate or cesium carbonate in an inert solvent such as an amide like DMF or NMP or a ketone like acetone or butan-2-one, or with the respective alcohol under the conditions of the Mitsunobu reaction referred to above.
  • a halogen compound for example a bromide or iodide
  • a hydroxy group can be esterified to give a carboxylic acid ester or a sulfonic acid ester, or converted into a halide by treatment with a halogenating agent.
  • Halogen atoms can also be introduced by means of suitable halogenating agents which replace a hydrogen atom in the starting compound, for example by means of elemental bromine, sulfuryl chloride or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), which introduce a bromine, chlorine and fluorine substituent, respectively, for example in the 4-position of a compound of the formula IIb.
  • a halogen atom can generally be replaced with a variety of groups in substitution reactions which may also be transition-metal catalyzed reactions.
  • a nitro group can be reduced to an amino group, for example by catalytic hydrogenation.
  • An amino group can be modified under standard conditions for alkylation, for example by reaction with a halogen compound or by reductive amination of a carbonyl compound, or for acylation or sulfonylation, for example by reaction with an activated carboxylic acid or a carboxylic acid derivate like an acid chloride or anhydride or a sulfonic acid chloride.
  • a carboxylic ester group can be hydrolyzed under acidic or basic conditions to give a carboxylic acid.
  • An acid group can be activated or converted into a reactive derivative as outlined above and reacted with an alcohol or an amine or ammonia to give an ester or amide.
  • a primary amide can be dehydrated to give a nitrile.
  • a sulfur atom in an alkyl-S— group or in a heterocyclic ring can be oxidized with a peroxide like hydrogen peroxide or a peracid to give a sulfoxide moiety S(O) or a sulfone moiety S(O) 2 .
  • a carboxylic acid group, carboxylic acid ester group and a ketone group can be reduced to an alcohol, for example with a complex hydride such al lithium aluminium hydride, lithium borohydride or sodium borohydride, or reacted with an organometallic compound or a Grignard compound to give an alcohol.
  • Primary and secondary hydroxy groups can also be oxidized to the oxo groups.
  • All reactions in the preparation of the compounds of the formula I are known per se and can be carried out in a manner familiar to a person skilled in the art according to, or analogously to, procedures which are described in the standard literature, for example in Houben-Weyl, Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley & Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2. ed. (1999), John Wiley & Sons, and the references quoted therein.
  • Another subject of the present invention are the novel starting compounds and intermediates occurring in the synthesis of the compounds of the formula I, including the compounds of the formulae Ia, Ib, Ic, II, IIc, III, IIIa, IV, V and VIII, wherein the groups A, D, E, L, G, J, T, R 2 , R 10 , R 10a , R 30 , R 40 , R 50 and R 60 are defined as above, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their salts, and solvates of any of them, and their use as synthetic intermediates or starting compounds.
  • a subject of the invention are in particular the novel specific starting compounds and intermediates described herein. Independently thereof whether they are described as a free compound and/or as a specific salt, they are a subject of the invention both in the form of the free compounds and in the form of their salts, and if a specific salt is described, additionally in the form of this specific salt.
  • the compounds of the formula I inhibit the protease cathepsin A as can be demonstrated in the pharmacological test described below and in other tests which are known to a person skilled in the art.
  • the compounds of the formula I and their physiologically acceptable salts and solvates therefore are valuable pharmaceutical active compounds.
  • cardiovascular diseases such as heart failure including systolic heart failure, diastolic heart failure, diabetic heart failure and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction including left ventricular dysfunction after myocardial infarction, cardiac hypertrophy, myocardial remodeling including myocardial remodeling after infarction or after cardiac surgery, valvular heart diseases, vascular hypertrophy, vascular remodeling including vascular stiffness, hypertension including pulmonary hypertension, portal hypertension and systolic hypertension, atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis, thrombosis and vascular permeability disorders, ischemia and/or reperfusion damage including ischemia and/or reperfusion damage of the heart and ischemia and/or reperfusion damage of the retina, inflammation and inflammatory diseases such as rheumatoid arthritis and osteoarthritis, renal
  • the treatment of diseases is to be understood as meaning both the therapy of existing pathological changes or malfunctions of the organism or of existing symptoms with the aim of relief, alleviation or cure, and the prophylaxis or prevention of pathological changes or malfunctions of the organism or of symptoms in humans or animals which are susceptible thereto and are in need of such a prophylaxis or prevention, with the aim of a prevention or suppression of their occurrence or of an attenuation in the case of their occurrence.
  • the compounds of the formula I and their physiologically acceptable salts and solvates can therefore be used in animals, in particular in mammals and specifically in humans, as a pharmaceutical or medicament on their own, in mixtures with one another or in the form of pharmaceutical compositions.
  • a subject of the present invention also are the compounds of the formula I and their physiologically acceptable salts and solvates for use as a pharmaceutical, as well as pharmaceutical compositions and medicaments which comprise an efficacious dose of at least one compound of the formula I and/or a physiologically acceptable salt thereof and/or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically innocuous, or nonhazardous, vehicles and/or excipients, and optionally one or more other pharmaceutical active compounds.
  • a pharmaceutically acceptable carrier i.e. one or more pharmaceutically innocuous, or nonhazardous, vehicles and/or excipients, and optionally one or more other pharmaceutical active compounds.
  • a subject of the present invention furthermore are the compounds of the formula I and their physiologically acceptable salts and solvates for use in the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of heart failure, myocardial infarction, cardiac hypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemia and/or reperfusion damage, or for cardioprotection, the use of the compounds of the formula I and their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of heart failure, myocardial infarction, cardiac hypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemia and/or reperfusion damage, or for cardioprotection, wherein the treatment of diseases comprises their therapy and prophylaxis as mentioned above, as well as their use for the manufacture of a medicament for the inhibition of
  • a subject of the invention also are methods for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of heart failure, myocardial infarction, cardiac hypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemia and/or reperfusion damage, or for cardioprotection, which comprise administering an efficacious amount of at least one compound of the formula I and/or a physiologically acceptable salt thereof and/or solvate thereof to a human or an animal which is in need thereof.
  • any one of the mentioned diseases for example the treatment of heart failure, myocardial infarction, cardiac hypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemia and/or reperfusion damage, or for cardioprotection, which comprise administering an efficacious amount of at least one compound of the formula I and/or a physiologically acceptable salt thereof and/or solvate thereof to a human or an animal which is in need thereof.
  • the compounds of the formula I and pharmaceutical compositions and medicaments comprising them can be administered enterally, for example by oral, sublingual or rectal administration, parenterally, for example by intravenous, intramuscular, subcutaneous or intraperitoneal injection or infusion, or by another type of administration such as topical, percutaneous, transdermal, intra-articular or intraocular administration.
  • the compounds of the formula I and their physiologically acceptable salts and solvates can also be used in combination with other pharmaceutical active compounds, wherein in such a combination use the compounds of the formula I and/or their physiologically acceptable salts and/or solvates and one or more other pharmaceutical active compounds can be present in one and the same pharmaceutical composition or in two or more pharmaceutical compositions for separate, simultaneous or sequential administration.
  • Examples of such other pharmaceutical active compounds are diuretics, aquaretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, renin inhibitors, beta blockers, digoxin, aldosterone antagonists, NO donors, nitrates, hydralazines, ionotropes, vasopressin receptor antagonists, soluble guanylate cyclase activators, statins, peroxisome proliferator-activated receptor-alpha (PPAR- ⁇ ) activators, peroxisome proliferator-activated receptor-gamma (PPAR- ⁇ ) activators, rosiglitazone, pioglitazone, metformin, sulfonylureas, glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase IV (DPPIV) inhibitors, insulins, anti-arrhythmics, endothelin receptor antagonists, calcium antagonists, phosphodiesterase inhibitor
  • the pharmaceutical compositions and medicaments according to the invention normally contain from about 0.5 to about 90 percent by weight of compounds of the formula I and/or physiologically acceptable salts and/or solvates thereof, and an amount of active ingredient of the formula I and/or its physiologically acceptable salt and/or solvate which in general is from about 0.2 mg to about 1.5 g, particularly from about 0.2 mg to about 1 g, more particularly from about 0.5 mg to about 0.5 g, for example from about 1 mg to about 0.3 g, per unit dose. Depending on the kind of the pharmaceutical composition and other particulars of the specific case, the amount may deviate from the indicated ones.
  • the production of the pharmaceutical compositions and medicaments can be carried out in a manner known per se.
  • the compounds of the formula I and/or their physiologically acceptable salts and/or solvates are mixed together with one or more solid or liquid vehicles and/or excipients, if desired also in combination with one or more other pharmaceutical active compounds such as those mentioned above, and brought into a suitable form for dosage and administration, which can then be used in human medicine or veterinary medicine.
  • excipients suitable organic and inorganic substances can be used which do not react in an undesired manner with the compounds of the formula I.
  • excipients, or additives which can be contained in the pharmaceutical compositions and medicaments, lubricants, preservatives, thickeners, stabilizers, disintegrants, wetting agents, agents for achieving a depot effect, emulsifiers, salts, for example for influencing the osmotic pressure, buffer substances, colorants, flavorings and aromatic substances may be mentioned.
  • vehicles and excipients are water, vegetable oils, waxes, alcohols such as ethanol, isopropanol, 1,2-propanediol, benzyl alcohols, glycerol, polyols, polyethylene glycols or polypropylene glycols, glycerol triacetate, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose or starch like corn starch, sodium chloride, stearic acid and its salts such as magnesium stearate, talc, lanolin, petroleum jelly, or mixtures thereof, for example saline or mixtures of water with one or more organic solvents such as mixtures of water with alcohols.
  • alcohols such as ethanol, isopropanol, 1,2-propanediol, benzyl alcohols, glycerol, polyols, polyethylene glycols or polypropylene glycols, glycerol triacetate, polyvinylpyrrolidone,
  • pharmaceutical forms such as, for example, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, including oily, alcoholic or aqueous solutions, syrups, juices or drops, furthermore suspensions or emulsions, can be used.
  • solutions including oily, alcoholic or aqueous solutions, syrups, juices or drops, furthermore suspensions or emulsions
  • parenteral use for example by injection or infusion
  • pharmaceutical forms such as solutions, for example aqueous solutions
  • pharmaceutical forms such as ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions or powders can be used.
  • Further suitable pharmaceutical forms are, for example, implants and patches and forms adapted to inhalation.
  • the compounds of the formula I and their physiologically acceptable salts can also be lyophilized and the obtained lyophilizates used, for example, for the production of injectable compositions.
  • liposomal compositions are suitable.
  • the pharmaceutical compositions and medicaments can also contain one or more other active ingredients and/or, for example, one or more vitamins.
  • the dosage of the compounds of the formula I depends on the circumstances of the specific case and is adjusted by the physician according to the customary rules and procedures. It depends, for example, on the compound of the formula I administered and its potency and duration of action, on the nature and severity of the individual syndrome, on the sex, age, weight and the individual responsiveness of the human or animal to be treated, on whether the treatment is acute or chronic or prophylactic, or on whether further pharmaceutical active compounds are administered in addition to a compound of the formula I.
  • a dose from about 0.1 mg to about 100 mg per kg per day, in particular from about 1 mg to about 20 mg per kg per day, for example from about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight), is administered.
  • the daily dose can be administered in the form of a single dose or divided into a number of individual doses, for example two, three or four individual doses.
  • the administration can also be carried out continuously, for example by continuous injection or infusion. Depending on the individual behavior in a specific case, it may be necessary to deviate upward or downward from the indicated dosages.
  • the compounds of the formula I can also be employed as an aid in biochemical investigations or as a scientific tool or for diagnostic purposes, for example in in-vitro diagnoses of biological samples, if an inhibition of cathepsin A is intended.
  • the compounds of the formula I and their salts can also be used as intermediates, for example for the preparation of further pharmaceutical active substances.
  • TFA trifluoroacetic acid THF tetrahydrofuran TOTU O-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • example compounds containing a basic group were purified by preparative high pressure liquid chromatography (HPLC) on reversed phase (RP) column material and, as customary, the eluent was a gradient mixture of water and acetonitrile containing trifluoroacetic acid, they were in part obtained in the form of their acid addition salts with trifluoroacetic acid, depending on the details of the work-up such as evaporation or lyophilization conditions.
  • HPLC high pressure liquid chromatography
  • RP reversed phase
  • the prepared compounds were in general characterized by spectroscopic data and chromatographic data, in particular mass spectra (MS) and HPLC retention times (Rt; in min) which were obtained by combined analytical HPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance (NMR) spectra. Unless specified otherwise, 1 H-NMR spectra were recorded at 500 MHz in D 6 -DMSO as solvent at 298 K.
  • the chemical shift ⁇ (in ppm), the number of hydrogen atoms (H), and the multiplicity (s: singlet, d: doublet, dd: doublet of doublets, t: triplet, q: quartet, m: multiplet) of the peaks as determined from the graphically depicted spectra are given.
  • the MS characterization in general the mass number (m/z) of the peak of the molecular ion [M], for example [M + ], or of a related ion such as the ion [M+1], for example [(M+1) + ], i.e.
  • the ionization method was electrospray ionization (ES).
  • ES electrospray ionization
  • Cathepsin L activity was then stopped by the addition of the cysteine protease inhibitor E-64 (N-(trans-epoxysuccinyl)-L-leucine-4-guanidinobutylamide; Sigma-Aldrich, #E3132; dissolved in activation buffer/DMSO) to a final concentration of 10 ⁇ M.
  • E-64 N-(trans-epoxysuccinyl)-L-leucine-4-guanidinobutylamide
  • E3132 N-(trans-epoxysuccinyl)-L-leucine-4-guanidinobutylamide
  • activation buffer/DMSO activation buffer/DMSO
  • the activated cathepsin A was diluted in assay buffer (25 mM MES, pH 5.5, containing 5 mM DTT) and mixed with the test compound (dissolved in assay buffer containing (v/v) 3% DMSO) or, in the control experiments, with the vehicle in a multiple assay plate. After incubation for 15 min at room temperature, as substrate then bradykinin carrying an N-terminal ®Bodipy FL (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl) label (JPT Peptide Technologies GmbH; dissolved in assay buffer) was added to the mixture.
  • assay buffer 25 mM MES, pH 5.5, containing 5 mM DTT
  • cathepsin A was 833 ng/ml and the final concentration of labeled bradykinin 2 ⁇ M.
  • stop buffer 130 mM 2-(4-(2-hydroxy-ethyl)-piperazin-1-yl)-ethanesulfonic acid, pH 7.4, containing (v/v) 0.013% ®Triton X-100, 0.13% Coating Reagent 3 (Caliper Life Sciences), 6.5% DMSO and 20 ⁇ M ebelactone B (Sigma, #E0886)).
  • the in vivo pharmacological activity of the compounds of the invention can be investigated, for example, in the model of DOCA-salt sensitive rats with unilateral nephrectomy.
  • unilateral nephrectomy of the left kidney (UNX) is performed on Sprague Dawley rats of 150 g to 200 g of body weight. After the operation as well as at the beginning of each of the following weeks 30 mg/kg of body weight of DOCA (desoxycorticosterone acetate) are administered to the rats by subcutaneous injection.
  • DOCA desoxycorticosterone acetate
  • the nephrectomized rats treated with DOCA are supplied with drinking water containing 1% of sodium chloride (UNX/DOCA rats).
  • the UNX/DOCA rats develop high blood pressure, endothelial dysfunction, myocardial hypertrophy and fibrosis as well as renal dysfunction.
  • the rats are treated orally by gavage in two part administrations at 6 a.m. and 6 p.m. with the daily dose of the test compound (for example 10 mg/kg of body weight dissolved in vehicle) or with vehicle only, respectively.
  • the rats receive normal drinking water and are treated with vehicle only.
  • systolic blood pressure (SBP) and heart rate (HR) are measured non-invasively via the tail cuff method.
  • SBP systolic blood pressure
  • HR heart rate
  • 24 h urine is collected on metabolic cages. Endothelial function is assessed in excised rings of the thoracic aorta as described previously (W. Linz et al., JRAAS (Journal of the renin-angiotensin-aldosterone system) 7 (2006), 155-161).
  • JRAAS Journal of the renin-angiotensin-aldosterone system

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Abstract

The present invention relates to compounds of the formula I,
Figure US20140135328A1-20140515-C00001
wherein A, D, E, L, G, R10, R30, R40, R50 and R60 have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. They are inhibitors of the protease cathepsin A, and are useful for the treatment of diseases such as atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 13/357,245, filed Jan. 24, 2012, which claims benefit of U.S. Provisional Application No. 61/486,945, filed May 17, 2011, which claims priority of European Patent Application No. 11305078.5, filed Jan. 26, 2011, which are incorporated herein by reference in their entirety.
  • The present invention relates to compounds of the formula I,
  • Figure US20140135328A1-20140515-C00002
  • wherein A, D, E, L, G, R10, R30, R40, R50 and R60 have the meanings indicated below, which are valuable pharmaceutical active compounds. They are inhibitors of the protease cathepsin A, and are useful for the treatment of diseases such as atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.
  • Cathepsin A (EC=3.4.16.5; gene symbol CTSA) is a protease also known as lysosomal carboxypeptidase A or protective protein. It belongs to a family of serine carboxypeptidases which contains only two other mammalian representatives, retinoid-inducible serine carboxypeptidase and vitellogenic carboxypeptidase-like protein. Within the cell cathepsin A resides in lysosomes where it forms a high molecular weight complex with beta-galactosidase and neuraminidase. The interaction of cathepsin A with these glycosidases is essential for their correct routing to the lysosome and protects them from intralysosomal proteolysis. A deficiency of cathepsin A resulting from various mutations in the ctsa gene leads to a secondary deficiency of beta-galactosidase and neuraminidase that is manifest as the autosomal recessive lysosomal storage disorder galactosialidosis (cf. A. d'Azzo et al., in “The Metabolic and Molecular Bases of Inherited Disease”, vol. 2 (1995), 2835-2837). The majority of identified mutations in ctsa are missense mutations affecting the folding or the stability of the protein. None of them was shown to occur in the active site of the enzyme (G. Rudenko et al., Proc. Natl. Acad. Sci. USA 95 (1998), 621-625). Accordingly, the lysosomal storage disorder can be corrected with catalytically inactive cathepsin A mutants (N. J. Galjart et al., J. Biol. Chem. 266 (1991), 14754-14762). The structural function of cathepsin A is therefore separable from its catalytic activity. This is also underscored by the observation that in contrast to mice deficient in the ctsa gene, mice carrying a catalytically inactivating mutation in the ctsa gene do not develop signs of the human disease galactosialidosis (R. J. Rottier et al., Hum. Mol. Genet. 7 (1998), 1787-1794; V. Seyrantepe et al., Circulation 117 (2008), 1973-1981).
  • Cathepsin A displays carboxypeptidase activity at acidic pH and deamidase and esterase activities at neutral pH against various naturally occurring bioactive peptides. In vitro studies have indicated that cathepsin A converts angiotensin I to angiotensin 1-9 and bradykinin to bradykinin 1-8, which is the ligand for the bradykinin B1 receptor. It hydrolyzes endothelin-1, neurokinin and oxytocin, and deamidates substance P (cf. M. Hiraiwa, Cell. Mol. Life. Sci. 56 (1999), 894-907). High cathepsin A activity has been detected in urine, suggesting that it is responsible for tubular bradykinin degradation (M. Saito et al., Int. J. Tiss. Reac. 17 (1995), 181-190). However, the enzyme can also be released from platelets and lymphocytes and is expressed in antigen-presenting cells where it might be involved in antigen processing (W. L. Hanna et al., J. Immunol. 153 (1994), 4663-4672; H. Ostrowska, Thromb. Res. 86 (1997), 393-404; M. Reich et al., Immunol. Lett. (online Nov. 30, 2009)). Immunohistochemistry of human organs revealed prominent expression in renal tubular cells, bronchial epithelial cells, Leydig's cells of the testis and large neurons of the brain (O. Sohma et al., Pediatr. Neurol. 20 (1999), 210-214). It is upregulated during differentiation of monocytes to macrophages (N. M. Stamatos et al., FEBS J. 272 (2005), 2545-2556). Apart from structural and enzymatic functions, cathepsin A has been shown to associate with neuraminidase and an alternatively spliced beta-galactosidase to form the cell-surface laminin and elastin receptor complex expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes and certain cancer cell types (A. Hinek, Biol. Chem. 377 (1996), 471-480).
  • The importance of cathepsin A for the regulation of local bradykinin levels has been demonstrated in animal models of hypertension. Pharmacological inhibition of cathepsin A activity increased renal bradykinin levels and prevented the development of salt-induced hypertension (H. Ito et al., Br. J. Pharmacol. 126 (1999), 613-620). This could also be achieved by antisense oligonucleotides suppressing the expression of cathepsin A (I. Hajashi et al., Br. J. Pharmacol. 131 (2000), 820-826). Besides in hypertension, beneficial effects of bradykinin have been demonstrated in various further cardiovascular diseases and other diseases (cf. J. Chao et al., Biol. Chem. 387 (2006), 665-75; P. Madeddu et al., Nat. Clin. Pract. Nephrol. 3 (2007), 208-221). Key indications of cathepsin A inhibitors therefore include atherosclerosis, heart failure, cardiac infarction, cardiac hypertrophy, vascular hypertrophy, left ventricular dysfunction, in particular left ventricular dysfunction after myocardial infarction, renal diseases such as renal fibrosis, renal failure and kidney insufficiency; liver diseases such as liver fibrosis and liver cirrhosis, diabetes complications such as nephropathy, as well as organ protection of organs such as the heart and the kidney.
  • As indicated above, cathepsin A inhibitors can prevent the generation of the bradykinin B1 receptor ligand bradykinin 1-8 (M. Saito et al., Int. J. Tiss. Reac. 17 (1995), 181-190). This offers the opportunity to use cathepsin A inhibitors for the treatment of pain, in particular neuropathic pain, and inflammation, as has been shown for bradykinin B1 receptor antagonists (cf. F. Marceau et al., Nat. Rev. Drug Discov. 3 (2004), 845-852). Cathepsin A inhibitors can further be used as anti-platelet agents as has been demonstrated for the cathepsin A inhibitor ebelactone B, a propiolactone derivative, which suppresses platelet aggregation in hypertensive animals (H. Ostrowska et al., J. Cardiovasc. Pharmacol. 45 (2005), 348-353).
  • Further, like other serine proteases such as prostasin, elastase or matriptase, cathepsin A can stimulate the amiloride-sensitive epithelial sodium channel (ENaC) and is thereby involved in the regulation of fluid volumes across epithelial membranes (cf. C. Planes et al., Curr. Top. Dev. Biol. 78 (2007), 23-46). Thus, respiratory diseases can be ameliorated by the use of cathepsin A inhibitors, such as cystic fibrosis, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections and lung carcinoma. Cathepsin A modulation in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
  • Besides for the above-mentioned compound ebelactone B, an inhibitory effect on cathepsin A has been found for certain dipeptidic phenylalanine derivatives which are described in JP 2005/145839. There is a need for further compounds which inhibit cathepsin A and offer an opportunity for the treatment of the mentioned diseases and further diseases in which cathepsin A plays a role. The present invention satisfies this need by providing the oxygen-substituted 3-heteroaroylamino-propionic acid derivatives of the formula I defined below.
  • Certain compounds in which a 3-heteroaroylamino-propionic acid moiety can be present, have already been described. For example, in WO 2006/076202 amine derivatives, which modulate the activity of steroid nuclear receptors, are described which carry on the nitrogen atom of the amine function a heteroaroyl group and a further group which is defined very broadly. In US 2004/0072802 broadly-defined beta-amino acid derivatives are described which carry an acyl group on the beta-amino group and are inhibitors of matrix metalloproteases and/or tumor necrosis factor. In WO 2009/080226 and WO 2009/080227, which relate to antagonists of the platelet ADP receptor P2Y12 and inhibit platelet aggregation, pyrazoloylamino-substituted carboxylic acid derivatives are described which, however, additionally carry a carboxylic acid derivative group on the carbon atom carrying the pyrazoloylamino group. Other pyrazoloylamino-substituted compounds, in which the nitrogen atom of the amino group is connected to a ring system and which are inhibitors of the blood clotting enzymes factor Xa and/or factor Vila, are described in WO 2004/056815.
  • A subject of the present invention is a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them,
  • Figure US20140135328A1-20140515-C00003
  • wherein
    A is chosen from the series consisting of C(R1) and N;
    D is chosen from the series consisting of C(R2) and N;
    E is chosen from the series consisting of C(R3) and N;
    L is chosen from the series consisting of C(R4) and N;
    where at least one and at most two of A, D, E or L is N;
    G is chosen from the series consisting of R71—O—C(O)—, R72—N(R73)—C(O)— and tetrazol-5-yl;
    R1 is chosen from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, HO—, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m— and NC—;
    R2 is chosen from the series consisting of hydrogen, halogen, (C1-C7)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-CO—, (C1-C6)-alkyl-CO—HN—, —NR12R13, Het2′ (C3-C7)-cycloalkyl-CsH2s— and Ar—CsH2s—, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3;
    R3 is chosen from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-S(O)m—, Het4—(O)t—, —NR12R13, Het2, R11—O—, R12—N(R13)—C(O)—O—, and Het2-C(O)—O— and NC—, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1;
    R4 is chosen from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, HO—, NR12R13, Het2;
    R10 is chosen from the series consisting hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, HO—, —NR12R13, Het2, phenyl-CsH2s—(O)t—, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1;
    or R1 and R2 or R2 and R3 or form pyridyl;
    or R1 and R2 are —C((C1-C3)-alkyl)═N—N((C1-C3)-alkyl)-;
    • or R2 and R3 are —NH—CH═N—;
  • with the proviso that one of R1, R2, R3, R4 or R10 is a cyclic substituent;
    R11 is chosen from the series consisting of hydrogen, R14, (C3-C7)-cycloalkyl, Ar and Het3;
    R12 and R13 are independently of each other chosen from the series consisting of hydrogen and R15;
    R14 is (C1-C10)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Ar, Het1, Het3, NC—, H2N—C(O)—, (C1-C4)-alkyl-NH—C(O)—, di((C1-C4)-alkyl)N—C(O)—, Het1-C(O)—, (C1-C4)-alkyl-C(O)—NH— and (C1-C4)-alkyl-S(O)m—;
    R15 is (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting halogen, HO— and (C1-C6)-alkyl-O—;
  • R16 is (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of HO—, (C1-C4)-alkyl-O— and NC—;
  • R30 is chosen from the series consisting of R31, (C3-C7)-cycloalkyl, R32—CuH2u— and Het3-CuH2u—, wherein u is an integer chosen from the series consisting of 0, 1, 2 and 3;
    R31 is (C1-C10)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m— and NC—;
    R32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, HO—, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, (C1-C4)-alkyl-NH—S(O)2—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, (C1-C6)-alkyl-NH—, di((C1-C6)-alkyl)N—, Het1, (C1-C4)-alkyl-C(O)—NH—, Ar—C(O)—NH—, (C1-C4)-alkyl-S(O)2—NH— and NC—;
    R33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, (C1-C4)-alkyl-NH—S(O)2—, di((C1-C4)-alkyl)N—S(O)2— and NC—;
    R40 is chosen from the series consisting of hydrogen and (C1-C4)-alkyl;
    or R30 and R40 together are (CH2)x which is optionally substituted by one or more identical or different (C1-C4)-alkyl substituents, wherein x is an integer chosen from the series consisting of 2, 3, 4 and 5;
    R50 is chosen from the series consisting of hydrogen, (C1-C6)-alkyl, HO— and (C1-C6)-alkyl-O—;
    R60 is chosen from the series consisting of hydrogen and (C1-C6)-alkyl;
    or R50 and R60 together are (CH2)y which is optionally substituted by one or more identical or different (C1-C4)-alkyl substituents, wherein y is an integer chosen from the series consisting of 2, 3, 4 and 5;
    R71 is chosen from the series consisting of hydrogen and (C1-C8)-alkyl which is optionally substituted by one or more identical or different substituents chosen from the series consisting (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—;
    R72 is chosen from the series consisting of hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, —CH2—(CH2)b—(C3-C6)-cycloalkyl, Het4 and —(CH2)b-Het4, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—, NC—, N((C1-C4)-alkyl)2 and b is 0, 1 or 2; R73 is chosen from the series consisting of hydrogen, (C1-C6)-alkyl; or
    R72 and R73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—;
    Ar, independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C6)-alkyl, HO—(C1-C6)-alkyl, Het4, —(CH2)x-Phenyl, (C1-C6)-alkyl-O—, (C3-C7)-cycloalkyl-(CH2)x—O—, —CF3, —CO—(C1-C6)-alkyl, —NR12R13, Het2, —CO—NR12R13, CO-Het2, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2— and NC; and wherein phenyl may be substituted by —CH═CH—CH═CH—, —O—CH2—O—, —O—CH2—CH2—O—, —O—CF2—O— or —N((C1-C3)-alkyl)-CH═CH—;
  • Het1, independently of each other group Het1, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het1 is bonded and optionally one or two identical or different further ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O—, oxo and NC—;
  • Het2 is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises a ring nitrogen atom via which Het2 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—;
  • Het3, independently of each other group Het3, is a saturated 4-membered to 7-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine, (C1-C4)-alkyl and oxo;
  • Het4, independently of each other group Het4, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O—, oxo and NC—;
  • m, independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2;
    wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (C1-C4)-alkyl;
    wherein all alkyl, CsH2s, CuH2u, (CH2)x and (CH2)y groups, independently of each other, and independently of any other substituents, are optionally substituted by one or more fluorine substituents.
  • If structural elements such as groups, substituents or numbers, for example, can occur several times in the compounds of the formula I, they are all independent of each other and can in each case have any of the indicated meanings, and they can in each case be identical to or different from any other such element. In a dialkylamino group, for example, the alkyl groups can be identical or different.
  • Alkyl groups, i.e. saturated hydrocarbon residues, can be linear (straight-chain) or branched. This also applies if these groups are substituted or are part of another group, for example an alkyl-O— group (alkyloxy group, alkoxy group) or an HO-substituted alkyl group (hydroxyalkyl group). Depending on the respective definition, the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or 1, 2, 3, 4, 5, 6, 7 or 8, or 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, or 1, for example. In one embodiment of the invention, a (C1-C10-alkyl group present in the compounds of the formula I is a (C1-C8)-alkyl group, in another embodiment a (C1-C6)-alkyl group, in another embodiment a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a (C2-C3)-alkyl group, in another embodiment a methyl group. In one embodiment of the invention, a (C1-C8)-alkyl group present in any position of the compounds of the formula I is a (C1-C6)-alkyl group, in another embodiment a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a (C2-C3)-alkyl group, in another embodiment a methyl group, where any (C1-C8)-alkyl group present in the compounds of the formula I can independently of each other (C1-C8)-alkyl group be a group of any of these embodiments. In one embodiment of the invention, a (C1-C6)-alkyl group present in any position of the compounds of the formula I is a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a (C2-C3)-alkyl group, in another embodiment a methyl group, where any (C1-C6)-alkyl group present in the compounds of the formula I can independently of each other (C1-C6)-alkyl group be a group of any of these embodiments. In one embodiment of the invention, a (C1-C4)-alkyl group present in any position of the compounds of the formula I is a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a (C2-C3)-alkyl group, in another embodiment a methyl group, where any (C1-C4)-alkyl group present in the compounds of the formula I can independently of each other (C1-C4)-alkyl group be a group of any of these embodiments. Examples of alkyl groups are methyl, ethyl, propyl groups including propyl (i.e. n-propyl) and isopropyl, butyl groups including butyl (i.e. n-butyl), sec-butyl, isobutyl and tert-butyl, pentyl groups including pentyl (i.e. n-pentyl), 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, hexyl groups including hexyl (i.e. n-hexyl), 3,3-dimethylbutyl and isohexyl, heptyl groups including heptyl (i.e. n-heptyl), octyl groups including octyl (i.e. n-octyl), nonyl groups including nonyl (i.e. n-nonyl), and decyl groups including decyl (i.e. n-decyl). Examples of alkyl-O— groups are methoxy, ethoxy, propoxy (i.e. n-propoxy), isopropoxy, butoxy (i.e. n-butoxy), isobutoxy, tert-butoxy, pentoxy (i.e. n-pentoxy). Examples of alkyl-S(O)m— are methylsulfanyl-(CH3—S—), methanesulfinyl-(CH3—S(O)—), methanesulfonyl(CH3—S(O)2—), ethylsulfanyl-(CH3—CH2-S—), ethanesulfinyl-(CH3—CH2—S(O)—), ethanesulfonyl(CH3—CH2—S(O)2—), 1-methylethylsulfanyl-((CH3)2CH—S—), 1-methylethanesulfinyl-((CH3)2CH—S(O)—), 1-methylethanesulfonyl((CH3)2CH—S(O)2—). In one embodiment of the invention the number m is chosen from 0 and 2, wherein all numbers m are independent of each other and can be identical or different. In another embodiment the number m in any of its occurrences is, independently of its meaning in other occurrences, 0. In another embodiment the number m in any of its occurrences is, independently of its meaning in other occurrences, 2.
  • A substituted alkyl group can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound. The prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound, applies in general with respect to the definitions of all groups in the compounds of the formula I. In one embodiment of the invention, an individual carbon atom in any alkyl group in the compounds of the formula I, as well as in other groups such as cycloalkyl groups and heterocyclic groups, for example, independently of any other carbon atom does not carry more than one substituent which is bonded via an oxygen atom, nitrogen atom or sulfur atom, such as HO—, (C1-C4)-alkyl-O— or (C1-C4)-alkyl-S(O)m-substituents, for example. An alkyl group which is optionally substituted by one or more fluorine substituents can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by one, two, three, four, five, six, seven, eight, nine, ten or eleven fluorine substituents, or by one, two, three, four, five, six or seven fluorine substituents, or by one, two, three, four or five fluorine substituents, or by one, two or three fluorine substituents, which can be located in any positions. For example, in a fluoro-substituted alkyl group one or more methyl groups can carry three fluorine substituents each and be present as trifluoromethyl groups, and/or one or more methylene groups (CH2) can carry two fluorine substituents each and be present as difluoromethylene groups. The explanations with respect to the substitution of a group by fluorine also apply if the group additionally carries other substituents and/or is part of another group, for example of an alkyl-O— group. Examples of fluoro-substituted alkyl groups are trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl and heptafluoroisopropyl. Examples of fluoro-substituted alkyl-O— groups are trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy. Examples of fluoro-substituted alkyl-S(O)m— groups are trifluoromethylsulfanyl-(CF3—S—), trifluoromethanesulfinyl-(CF3—S(O)—) and trifluoromethanesulfonyl(CF3—S(O)2—).
  • The above explanations with respect to alkyl groups apply correspondingly to alkanediyl groups (divalent alkyl groups) including the divalent groups CsH2s, CuH2u, (CH2)x and (CH2)y. Also the alkyl part of a substituted alkyl group may be regarded as an alkanediyl group. Thus, alkanediyl groups can also be linear or branched, the bonds to the adjacent groups can be located in any positions and can start from the same carbon atom or from different carbon atoms, and they can be substituted by fluorine substituents. Examples of alkanediyl groups including the groups CsH2s and CuH2u and, as far they constitute polymethylene chains, the groups (CH2)x are —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—CH2—, —CH(CH3)—, —C(CH3)2—, —CH(CH3)—CH2—, —CH2—CH(CH3)—, —C(CH3)2—CH2—, —CH2—C(CH3)2—. Examples of fluoro-substituted alkanediyl groups, which can contain one, two, three, four, five or six fluorine substituents, or one, two, three or four fluorine substituents, or one or two fluorine substituents, for example, are —CHF—, —CF2— —CF2—CH2—, —CH2—CF2—, —CF2—CF2—, —CF(CH3)—, —C(CF3)2—, —C(CH3)2—CF2—, —CF2—C(CH3)2—.
  • The number of ring carbon atoms in a (C3-C7)-cycloalkyl group can be 3, 4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As regards the optional substitution of cycloalkyl groups by one or more (C1-C4)-alkyl substituents, they be unsubstituted, i.e. not carry alkyl substituents, or substituted, for example by one, two, three or four, or by one or two, identical or different (C1-C4)-alkyl substituents, for example by methyl groups, which substituents can be located in any positions. Examples of such alkyl-substituted cycloalkyl groups are 1-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-methylcyclopentyl, 2,3-dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl and 3,3,5,5-tetramethylcyclohexyl. As regards the optional substitution of cycloalkyl groups by one or more fluorine substituents, they can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by one, two, three, four, five, six, seven, eight, nine, ten or eleven fluorine substituents, or by one, two, three, four, five or six fluorine substituents, or by one, two, three or four fluorine substituents, or by one or two fluorine substituents. The fluorine substituents can be located in any positions of the cycloalkyl group and can also be located in an alkyl substituent on the cycloalkyl group. Examples of fluoro-substituted cycloalkyl groups are 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl, 4,4-difluorocyclohexyl and 3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkyl groups can also be substituted simultaneously by fluorine and alkyl. Examples of (C3-C7)-cycloalkyl-substituted alkyl groups, which can represent R11 or R30, for example, are cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-, 2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-, 1-cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-, 2-cyclohexylethyl-, 1-cycloheptylethyl-, 2-cycloheptylethyl-. The explanations with respect cycloalkyl groups apply correspondingly to divalent cycloalkyl groups (cycloalkanediyl groups), which can occur in case the two groups R30 and R40 together are (CH2), or the two groups R50 and R60 together are (CH2)y. Also the cycloalkyl part of a substituted cycloalkyl group may be regarded as a cycloalkanediyl group. Thus, for example, the bonds through which a cycloalkanediyl group is connected to the adjacent groups, can be located in any positions and can start from the same ring carbon atom, as in the case of the cycloalkanediyl group which is present if R30 and R40 together are (CH2)x or the two groups R50 and R60 together are (CH2)y, or from different ring carbon atoms.
  • In substituted phenyl groups the substituents can be located in any positions. In the case a the divalent substituents —O—CH2—O— (methylenedioxy) and —O—CF2-β-(difluoromethylenedioxy) which can be present on phenyl groups and aromatic heterocycles, the two oxygen atoms are bonded to adjacent ring carbon atoms of the phenyl group or the aromatic heterocycle and replace two hydrogen atoms of the parent system. In monosubstituted phenyl groups, the substituent can be located in the 2-position, the 3-position or the 4-position. In disubstituted phenyl groups, the substituents can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl groups, the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. If a phenyl group carries four substituents, some of which can be fluorine atoms, for example, the substituents can be located in 2,3,4,5-position, 2,3,4,6-position or 2,3,5,6-position. If a polysubstituted phenyl group carries different substituents, each substituent can be located in any suitable position, and the present invention comprises all positional isomers. The number of substituents in an optionally substituted phenyl group can be one, two, three, four or five. In one embodiment of the invention, an optionally substituted phenyl group, independently of any other optionally substituted phenyl group in a compound of the formula I, carries one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, identical or different substituents, and in another embodiment it is unsubstituted.
  • Likewise, in substituted heterocyclic groups, including aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R32, R33 and Ar, saturated and unsaturated 4-membered to 8-membered monocyclic heterocycles which can represent Het1, and saturated 4-membered to 7-membered monocyclic heterocycles which can represent Het2 and Het3, the substituents can be located in any positions and can be present on ring carbon atoms and/or on suitable ring nitrogen atoms. The present invention comprises all positional isomers. The number of substituents which can be present on substituted heterocycles in the compounds of the formula I, depends on the ring size, the number and type of the ring heteroatoms and the degree of unsaturation. In one embodiment of the invention, the number of identical or different substituents on any of the heterocyclic groups in the compounds of the formula I, independently of the number of substituents in any other occurrence of this group and the number of substituents in any other heterocyclic group in the compounds of the formula I, is one, two, three, four or five, in another embodiment one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. Ring nitrogen atoms which optionally carry a substituent, include ring nitrogen atoms in saturated heterocyclic rings other than those via which such a ring is bonded, and the ring nitrogen atom in 5-membered aromatic heterocycles such as pyrrole, imidazole or triazole, which in the parent heterocycle carry a hydrogen atom. In one embodiment of the invention, the substituents on any such ring nitrogen atoms in heterocyclic groups are chosen from those of the substituents specified in the definition of the respective group which are bonded via a carbon atom, for example from the series consisting of (C1-C6)-alkyl, (C3-C7)-cycloalkyl and R33, in another embodiment from the series consisting of (C1-C6)-alkyl and (C3-C7)-cycloalkyl, in the case of the aromatic heterocycle which can represent R32, from the series consisting of (C1-C6)-alkyl and (C3-C7)-cycloalkyl in the case of the aromatic heterocycle which can represent R33, and are (C1-C6)-alkyl in the case of the aromatic heterocycle which can represent Ar and (C1-C4)-alkyl in the case of Het1, Het2 and Het3. Generally, besides optionally carrying the substituents indicated in the definition of the respective group, suitable ring nitrogen atoms in heterocyclic groups in the compounds of the formula I, in particular aromatic heterocyclic groups such as the heterocyclic groups which can represent R32, R33 and Ar, for example the ring nitrogen atom in a pyridinyl group, can also carry an oxido substituent —O− and be present as an N-oxide.
  • The ring heteroatoms specified in the definitions of heterocyclic groups in the compounds of the formula I, including the aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R32, R33 and Ar and the heterocycles which represent Het1, Het2, Het3 and Het4 can generally be present in any combination and located in any suitable ring positions, provided that the resulting group and the compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound, as mentioned above. In one embodiment of the invention, two oxygen atoms in any heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions. In another embodiment, two ring heteroatoms in any non-aromatic heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions. In another embodiment, two ring heteroatoms chosen from the series consisting of N atoms which carry a hydrogen atom or a substituent and are bonded to the adjacent ring atoms by single bonds, O atoms and S atoms in a non-aromatic heterocycle cannot be present in adjacent ring positions. In an aromatic heterocycle the choice of ring heteroatoms and their positions is limited by the prerequisite that the ring is aromatic, i.e., it comprises a cyclic system of six delocalized pi electrons. Thus, for example, in an aromatic monocyclic 6-membered heterocycle only nitrogen atoms can occur as ring heteroatoms, and in an aromatic monocyclic 5-membered heterocycle only one ring heteroatom chosen from the series consisting of O atoms, S atoms and N atoms carrying a hydrogen atom or a substituent, can be present. An unsaturated heterocycle which can represent Het1, can be aromatic, for example in the case of a pyrrolyl, imidazolyl or triazolyl group which is bonded via a ring nitrogen atom and can represent Het1, or non-aromatic and comprise one or two double bonds within the ring which can be present in any positions. In one embodiment, a 4-membered heterocycle representing Het1 cannot be unsaturated. A heterocyclic group can be bonded via any ring carbon atom or via any suitable ring nitrogen atom, respectively, as indicated in the definition of the respective group. The group Het1 can be 4-membered, 5-membered, 6-membered or 7-membered or 8-membered. The groups Het2 and Het3 can be 4-membered, 5-membered, 6-membered or 7-membered.
  • Examples of aromatic heterocycles, from any one or more of which the aromatic 5-membered and 6-membered monocyclic heterocycles which can represent R32, R33 and Ar and, as far as applicable, the group Het1 are chosen in one embodiment of the invention, are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole ([1,3]oxazole), isoxazole ([1,2]oxazole), thiazole ([1,3]thiazole), isothiazole ([1,2]thiazole), [1,2,3]triazole, [1,2,4]triazole, [1,3,4]oxadiazole, pyridine, pyridazine, pyrimidine and pyrazine, which can all be bonded via any ring carbon atom or via any suitable ring nitrogen atom, and which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. Examples of specific residues of aromatic heterocycles, from any one or more of which the aromatic, 5-membered or 6-membered monocyclic heterocyclic residue which can represent R32, R33 or Ar and, as far as applicable, the group Het1, are chosen in one embodiment of the invention, are pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl (2-thienyl), thiophen-3-yl (3-thienyl), imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, [1,2,3]triazol-1-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl, [1,2,4]triazol-1-yl, [1,2,4]triazol-3-yl, [1,2,4]triazol-4-yl, [1,3,4]oxadiazol-2-yl, pyridin-2-yl (2-pyridyl), pyridin-3-yl (3-pyridyl), pyridin-4-yl (4-pyridyl), pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, and pyrazin-2-yl, which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • Examples of saturated heterocycles and non-aromatic unsaturated heterocycles, from any one or more of which the groups Het1, Het2, Het3 and Het4 are independently of each other chosen in one embodiment of the invention, as far as applicable with regard to the ring size and the degree of saturation, are azetidine, oxetane, thietane, pyrrolidine, 2,5-dihydro-1H-pyrrole, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, 4,5-dihydro-1H-imidazole, [1,3]dioxolane, oxazolidine, thiazolidine, piperidine, 1,2,3,6-tetrahydropyridine, tetrahydropyran, tetrahydrothiopyran, piperazine, [1,3]dioxane, [1,4]dioxane, morpholine, thiomorpholine, azepane, oxepane, thiepane, [1,3]diazepane, [1,4]diazepane, [1,4]oxazepane, [1,4]thiazepane and azocane, which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. Examples of specific residues of saturated and non-aromatic unsaturated heterocycles, from any one or more of which the groups Het1, Het2, Het3 and Het4 are independently of each other chosen in one embodiment of the invention, as far as applicable with regard to the ring size, the degree of saturation and the kind of the atom via which the residue is bonded are azetidin-1-yl, oxetan-3-yl, thietan-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, pyrazolidin-1-yl, pyrazolidin-4-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, 4,5-dihydro-1H-imidazol-2-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, piperazin-1-yl, piperazin-2-yl, [1,3]dioxan-2-yl, [1,3]dioxan-4-yl, [1,3]dioxan-5-yl, [1,4]dioxan-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepan-2-yl, oxepan-3-yl, oxepan-4-yl, [1,3]diazepan-1-yl, [1,4]diazepan-1-yl, [1,4]oxazepan-1-yl and [1,4]thiazepan-1-yl, which all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • Halogen is fluorine, chlorine, bromine or iodine. In one embodiment of the invention, halogen in any occurrence in the compounds of the formula I, independently of all other occurrences, is fluorine, chlorine or bromine, in another embodiment fluorine or chlorine, in another embodiment fluorine.
  • An oxo substituent, i.e. an oxygen atom which is bonded via a double bond, when bonded to a carbon atom, replaces two hydrogen atoms on the carbon atom of the parent system to which it is bonded. Thus, if a CH2 group is substituted by oxo, it becomes a carbonyl group (C(O), C═O). An oxo substituent cannot be present on a carbon atom in an aromatic ring. Besides on carbon atoms, oxo substituents can also be present on a ring sulfur atom in the group Het1, in particular if the group Het1 is saturated, and in the group Het3, to give the ring member S(O) (S═O, i.e. a sulfoxide group), if one oxo substituent is present on the sulfur atom, or the ring member S(O)2 (S(═O)2, i.e. a sulfone group), if two oxo substituents are present on the sulfur atom. As examples of heterocycles which can represent Het1 and Het3 and which carry oxo substituent a ring sulfur atom, 1,1-dioxo-tetrahydrothiophene, 1-oxo-thiomorpholine and 1,1-dioxo-thiomorpholine may be mentioned, which all are optionally substituted by further substituents such as (C1-C4)-alkyl substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below.
  • The present invention comprises all stereoisomeric forms of the compounds of the formula I, for example all enantiomers and diastereomers including cis/trans isomers. The invention likewise comprises mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers including cis/trans isomers, in all ratios. Asymmetric centers contained in the compounds of the formula I, for example in unsubstituted or substituted alkyl groups, can all independently of each other have the S configuration or the R configuration. The invention relates to enantiomers, both the levorotatory and the dextrorotatory antipode, in enantiomerically pure form and essentially enantiomerically pure form, for example with a molar ratio of the two enantiomers of 99:1 or greater, and in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. The invention likewise relates to diastereomers in the form of pure and essentially pure diastereomers and in the form of mixtures of two or more diastereomers in all ratios. The invention also comprises all cis/trans isomers of the compounds of the formula I in pure form and essentially pure form, for example with a molar ratio of the cis/trans isomers of 99:1 or greater, and in the form of mixtures of the cis isomer and the trans isomer in all ratios. Cis/trans isomerism can occur in substituted rings. The preparation of individual stereoisomers, if desired, can be carried out by resolution of a mixture according to customary methods, for example, by chromatography or crystallization, or by use of stereochemically uniform starting compounds in the synthesis or by stereoselective reactions. Optionally, before a separation of stereoisomers a derivatization can be carried out. The separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula I or at the stage of an intermediate in the course of the synthesis. The invention also comprises all tautomeric forms of the compounds of the formula I.
  • Physiologically acceptable salts, including pharmaceutically utilizable salts, of the compounds of the formula I generally comprise a nontoxic salt component. They can contain inorganic or organic salt components. Such salts can be formed, for example, from compounds of the formula I which contain an acidic group, for example a carboxylic acid group (hydroxycarbonyl group, HO—C(O)—), and nontoxic inorganic or organic bases. Suitable bases are, for example, alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia, organic amino compounds and quaternary ammonium hydroxides. Reactions of compounds of the formula I with bases for the preparation of the salts are in general carried out according to customary procedures in a solvent or diluent. Examples of salts of acidic groups thus are sodium, potassium, magnesium or calcium salts or ammonium salts which can also carry one or more organic groups on the nitrogen atom. Compounds of the formula I which contain a basic, i.e. protonatable, group, for example an amino group or a basic heterocycle, can be present in the form of their acid addition salts with physiologically acceptable acids, for example as salt with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, which in general can be prepared from the compounds of the formula I by reaction with an acid in a solvent or diluent according to customary procedures. If the compounds of the formula I simultaneously contain an acidic and a basic group in the molecule, the invention also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned. The present invention also comprises all salts of the compounds of the formula I which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange. The present invention also comprises all solvates of the compounds of the formula I and their salts, including physiologically acceptable solvates, such as hydrates, i.e. adducts with water, and adducts with alcohols like (C1-C4)-alkanols, as well as active metabolites of compounds of the formula I and prodrugs of the compounds of the formula I, i.e. compounds which in vitro may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds of the formula I, for example compounds which are converted by metabolic hydrolysis into a compound of the formula I, such as compounds in which a carboxylic acid group is present in esterified form or in the form of an amide.
  • In one embodiment of the invention, the group A is C(R1), in another embodiment A is N, in one embodiment of the invention, the group D is chosen from the series consisting of N, in another embodiment from the series consisting of C(R2), in one embodiment of the invention, the group E is chosen from the series consisting of N, in another embodiment from the series consisting of C(R3), in one embodiment of the invention, the group L is chosen from the series consisting of N, in another embodiment from the series consisting of C(R4), with the proviso that one or two of the groups A, D, E, L is N.
  • In another embodiment of the invention, the group A is N and the groups D, E and L are C(R2), C(R3) and C(R4).
  • In another embodiment of the invention, the group D is N and the groups A, E and L are C(R1), C(R3) and C(R4).
  • In another embodiment of the invention, the group E is N and the groups A, D and L are C(R1), C(R2) and C(R4).
  • In another embodiment of the invention, the group L is N and the groups A, D and E are C(R1), C(R2) and C(R3).
  • In another embodiment of the invention, the groups A and D are N and the groups E and L are C(R3) and C(R4).
  • In another embodiment of the invention, the group A and E is N and the groups D and L are C(R2) and C(R4).
  • In another embodiment of the invention, the group A and L is N and the groups D and E are C(R2) and C(R3).
  • In another embodiment of the invention, the group D and E is N and the groups A and L are C(R1) and C(R4).
  • In another embodiment of the invention, the group D and L is N and the groups A and E are C(R1) and C(R3).
  • In another embodiment of the invention, the group E and L is N and the groups A and D are C(R1) and C(R2).
  • In terms of formulae resulting from formula I by incorporation of meanings of A, D, E or L, in one embodiment of the invention a compound of the formula I is a compound of any one or more of formulae I-1 to I-7, for example a compound of formula I-1, or a compound of formula I-2, or a compound of formula I-3, or a compound of formula I-4, or a compound of formula I-5, or a compound of formula I-6, or a compound of formula I-7 in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein in the compounds of formulae I-1 to I-7 the groups A, D, E, G, R1, R2, R3, R10, R30, R40, R50 and R60 are defined as in the compounds of formula I in general or in any embodiment specified above or below.
  • Figure US20140135328A1-20140515-C00004
  • In one embodiment of the invention, the group G is chosen from the series consisting of R71—O—C(O)—, R72—N(R73)—C(O)— and tetrazol-5-yl, in another embodiment from the series consisting of R71—O—C(O)— and R72—N(R73)—C(O)—, in another embodiment G is R71—O—C(O)—, and in another embodiment G is R72—N(R73)—C(O)—.
  • In one embodiment of the invention, the group R1 is chosen from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, HO—, (C1-C6)-alkyl-O—, and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O— and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C1-C6)-alkyl and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, HO— and (C1-C6)-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen, (C1-C6)-alkyl and (C1-C6)-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen and (C1-C6)-alkyl, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen, fluorine and chlorine, and in another embodiment R1 is hydrogen. In one embodiment of the invention, a (C1-C6)-alkyl group occurring in R1 is a (C1-C4)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment it is methyl.
  • In one embodiment of the invention, the group R2 is chosen from the series consisting of (C1-C7)-alkyl and (C3-C7)-cycloalkyl-CsH2s—, in another embodiment from the series consisting of (C3-C7)-cycloalkyl-CsH2s— and Ar—CsH2s—, in another embodiment R2 is (C1-C7)-alkyl, in another embodiment R2 is (C3-C7)-cycloalkyl-CsH2s—, and in another embodiment R2 is Ar—CsH2s—. In one embodiment, s is an integer chosen from the series consisting of 0, 1 and 2, in another embodiment from the series consisting of 0 and 1, in another embodiment from the series consisting of 1 and 2, in another embodiment s is 0, and in another embodiment is 1. In one embodiment of the invention, R2 is Ar—CsH2s— and s is 0, i.e., R2 is the group Ar and the group D thus is the group N(Ar). In one embodiment, the divalent alkanediyl group CsH2s is a linear group. In one embodiment, a (C1-C7)-alkyl group representing R2 is a (C3-C7)-alkyl group, in another embodiment a (C3-C6)-alkyl group. In one embodiment, a (C3-C7)-cycloalkyl group occurring in R2 is a (C3-C6)-cycloalkyl group, in another embodiment a (C5-C6)-cycloalkyl group, in another embodiment a cyclopropyl group. In one embodiment, a group Ar occurring in R2 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom, in another embodiment from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment from the series consisting of phenyl, thiophenyl, pyridinyl and pyrimidinyl, in another embodiment from the series consisting of phenyl and thiophenyl, in another embodiment from the series consisting of phenyl, pyridinyl and pyrimidinyl, in another embodiment from the series consisting of phenyl and pyridinyl, and in another embodiment a group Ar occurring in R2 is phenyl, which groups all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Ar occurring in R2 is optionally substituted by one, two or three identical or different substituents, in another embodiment it is optionally substituted by one or two identical or different substituents, in another embodiment it is optionally substituted by one substituent, in another embodiment it is substituted by one, two or three identical or different substituents, in another embodiment it is substituted by one or two identical or different substituents, and in another embodiment it is substituted by one substituent. In one embodiment, the substituents which are optionally present on a group Ar occurring in R2, are chosen from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-S(O)m—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl and (C1-C6)-alkyl-S(O)m—, in another embodiment from the series consisting of halogen and (C1-C6)-alkyl, in another embodiment from the series consisting of halogen, in another embodiment from the series consisting of fluorine and chlorine, in another embodiment from the series consisting of fluorine, chlorine and methyl. In one embodiment of the invention, a (C1-C6)-alkyl group occurring in R2 is a (C1-C4)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment it is methyl.
  • Examples of groups Ar which can occur in R2, and from any one or more of which a group Ar occurring in R2 is chosen in one embodiment of the invention, are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-phenyl, 3,4-dichloro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 3-isopropyl-phenyl, 3-tert-butyl-phenyl, 4-tert-butyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 5-chloro-2-fluoro-3-methyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 5-chloro-2-trifluoromethyl-phenyl, 5-chloro-3-trifluoromethyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3-ethoxy-phenyl, 3-propoxy-phenyl, 3-isopropoxy-phenyl, 4-tert-butoxy-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-(2,2,2-trifluoroethoxy)-phenyl, 5-chloro-2-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 5-fluoro-3-isopropoxy-phenyl, 2-fluoro-3-trifluoromethoxy-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 3-methoxy-5-trifluoromethyl-phenyl, 2,3-methylenedioxy-phenyl, 2,3-difluoromethylenedioxy-phenyl, 3,4-methylenedioxy-phenyl, 3,4-difluoromethylenedioxy-phenyl, 3-methylsulfanyl-phenyl, 3-ethylsulfanyl-phenyl, 3-trifluoromethylsulfanyl-phenyl, 3-methanesulfonyl-phenyl, 3-ethanesulfonyl-phenyl, 3-sulfamoyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, thiophen-2-yl, thiophen-3-yl, 3-chloro-thiophen-2-yl, 4-chloro-thiophen-2-yl, 5-chloro-thiophen-2-yl, 4,5-dichloro-thiophen-2-yl, 5-chloro-thiophen-3-yl, 2,5-dichloro-thiophen-3-yl, 4-methyl-thiophen-2-yl, 5-methyl-thiophen-3-yl, 4,5-dimethyl-thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-chloro-pyridin-3-yl, 5-chloro-pyridin-2-yl, 6-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl, 2,6-dichloro-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-chloro-6-methoxy-pyridin-3-yl.
  • In one embodiment of the invention, the group R3 is chosen from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C1-C6)-alkyl and NC—, in another embodiment from the series consisting of hydrogen, halogen, (C1-C6)-alkyl and (C1-C6)-alkyl-O—, in another embodiment from the series consisting of hydrogen, halogen and (C1-C6)-alkyl, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen and (C1-C6)-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and chlorine, in another embodiment R3 is hydrogen, and in another embodiment R3 is (C1-C6)-alkyl. In one embodiment of the invention, a (C1-C6)-alkyl group occurring in R3 is a (C1-C4)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment it is methyl.
  • In one embodiment of the invention, the group R10 is chosen from the series consisting of R11—O— and R12—N(R13)—C(O)—O—, in another embodiment from the series consisting of R12—N(R13)—C(O)—O— and Het2-C(O)—O—, and in another embodiment R10 is R11—O—.
  • In one embodiment, the group Het2 which can occur in the group R2, R3, R4 or R10, is a saturated 4-membered to 6-membered, in another embodiment a 5-membered or 6-membered, in another embodiment a 5-membered, monocyclic heterocycle which, besides the ring nitrogen via which Het2 is bonded, optionally comprises one further ring heteroatom chosen from the series nitrogen, oxygen and sulfur. In one embodiment, the group Het2 which can occur in the group R2, R3, R4 or R10, does not comprise a further ring heteroatom besides the ring nitrogen atom via which Het2 is bonded. In one embodiment, the group Het2 which can occur in the group R2, R3, R4 or R10 is selected from the series pyrrolidine, piperidine and morpholine.
  • In one embodiment, the number of substituents which are optionally present on a group Het2 which can occur in group R2, R3, R4 or R10, is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het2 is unsubstituted. In one embodiment, the substituents which are optionally present on a group Het2 which can occur in the group R2, R3, R4 or R10, are chosen from the series consisting of fluorine, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—, in another embodiment from the series consisting of (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—, in another embodiment from the series consisting of (C1-C4)-alkyl and HO— and (C1-C4)-alkyl-O—, in another embodiment they are (C1-C4)-alkyl substituents, and in another embodiment they are HO— substituents.
  • In one embodiment of the invention, the group R11 is chosen from the series consisting of hydrogen, R14, (C3-C7)-cycloalkyl and Het3, in another embodiment from the series consisting of hydrogen and R14, in another embodiment from the series consisting of hydrogen, R14 and (C3-C7)-cycloalkyl, in another embodiment from the series consisting of (C3-C7)-cycloalkyl, Ar and Het3, in another embodiment from the series consisting of (C3-C7)-cycloalkyl and Het3, in another embodiment R11 is hydrogen, in another embodiment R11 is R14, and in another embodiment R11 is Ar. In one embodiment, a group Ar representing R11 is phenyl which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Ar representing R11 is optionally substituted by one, two or three identical or different substituents, in another embodiment it is optionally substituted by one or two identical or different substituents, in another embodiment it is optionally substituted by one substituent. In one embodiment, the substituents which are optionally present on a group Ar representing R11, are chosen from the series consisting of halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O—, in another embodiment from the series consisting of halogen and (C1-C4)-alkyl. In one embodiment, a (C3-C7)-cycloalkyl group representing R11 is a (C3-C6)-cycloalkyl group. In one embodiment, a group Het3 representing R11 is a saturated 4-membered to 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, in another embodiment it comprises one ring heteroatom chosen from the series consisting of nitrogen and oxygen, in another embodiment one ring heteroatom chosen from the series consisting of oxygen and sulfur, and in another embodiment it comprises one oxygen atom as ring heteroatom, wherein the heterocycle is bonded via a ring carbon atom and is optionally substituted by one, two, three or four, in another embodiment by one or two, identical or different substituents chosen from the series consisting of fluorine, (C1-C4)-alkyl and oxo, in another embodiment from the series consisting of fluorine and (C1-C4)-alkyl.
  • In one embodiment of the invention, the groups R12 and R13 are independently of each other chosen from the series consisting of hydrogen and R15, in another embodiment from the series consisting of R15 and Ar, and in another embodiment they are identical or different groups R15. In one embodiment, one of the groups R12 and R13 is chosen from the series consisting of R15 and Ar, and the other is a group R15. In one embodiment, a group Ar representing R12 or R13 is phenyl which is optionally substituted by one or two, in another embodiment by one, identical or different substituents chosen from the series consisting of halogen and (C1-C4)-alkyl, and in another embodiment it is unsubstituted phenyl.
  • In one embodiment of the invention, the (C1-C10)-alkyl group representing the group R14 is a (C1-C8)-alkyl group, in another embodiment a (C1-C7)-alkyl group, in another embodiment a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a methyl group, in another embodiment a (C4-C8)-alkyl group, in another embodiment a (C4-C7)-alkyl group, in another embodiment a (C5-C7)-alkyl group, in another embodiment a C6-alkyl group, wherein all these alkyl groups are linear or branched as applies to alkyl groups in the compounds of the formula I in general, and are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, an alkyl group representing R14 is unsubstituted, and in another embodiment it is substituted by one, two, three or four, in another embodiment by one, two or three, in another embodiment by one or two, in another embodiment by one substituent as indicated.
  • In one embodiment, a (C3-C7)-cycloalkyl group occurring as a substituent on an alkyl group representing R14 is a (C3-C6)-cycloalkyl group, in another embodiment it is a cyclopropyl group. In one embodiment, a group Ar occurring as a substituent on an alkyl group representing R14 is phenyl or an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur, and in another embodiment comprises one nitrogen atom as ring heteroatom and in the case of a 5-membered heterocycle one additional ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, and in another embodiment a group Ar occurring as a substituent in an alkyl group representing R14 is chosen from phenyl, pyrazolyl, isoxazolyl and thiazolyl, wherein all these groups Ar are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of optional substituents on a group Ar occurring as a substituent in an alkyl group representing R14 is one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Ar occurring as a substituent in an alkyl group representing R14, are chosen from the series consisting of halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O—, in another embodiment from the series consisting of halogen and (C1-C4)-alkyl, and in another embodiment they are (C1-C4)-alkyl groups.
  • In one embodiment, a group Het1 occurring as a substituent on an alkyl group representing R14 is a saturated or unsaturated 4-membered to 6-membered heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which comprises a ring nitrogen atom via which Het1 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Het1 occurring as a substituent on an alkyl group representing R14 does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het1 is bonded. In one embodiment, a group Het1 occurring as a substituent on an alkyl group representing R14 is saturated, in another embodiment it is unsaturated. In one embodiment, the number of substituents which are optionally present on a group Het1 occurring as a substituent on an alkyl group representing R14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Het1 occurring as a substituent on an alkyl group representing R14 are chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C1-C4)-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C1-C4)-alkyl and oxo, in another embodiment from the series consisting of (C1-C4)-alkyl and oxo, and in another embodiment they are oxo substituents. In one embodiment, the number of oxo substituents which are optionally present on a group Het1 occurring as a substituent on an alkyl group representing R14, is not greater than two, and in another embodiment it is not greater than one.
  • In one embodiment, a group Het1 occurring in the substituent Het1-C(O)— on an alkyl group representing R14 is a 4-membered to 6-membered heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which is saturated or unsaturated and comprises a ring nitrogen atom via which Het1 is bonded and optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, and which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Het1 occurring in the substituent Het1-C(O)— on an alkyl group representing R14 does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het1 is bonded. In one embodiment, a group Het1 occurring in the substituent Het1-C(O)— on an alkyl group representing R14 is saturated or comprises one double bond within the ring, and in another embodiment it is saturated. In one embodiment, the number of substituents which are optionally present on a group Het1 occurring in the substituent Het1-C(O)— on an alkyl group representing R14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Het1 occurring in the substituent Het1-C(O)— on an alkyl group representing R14 are chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C1-C4)-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C1-C4)-alkyl and oxo, in another embodiment from (C1-C4)-alkyl and oxo, in another embodiment they are oxo substituents, and in another embodiment they are (C1-C4)-alkyl substituents. In one embodiment, the number of oxo substituents which are optionally present on a group Het1 occurring in the substituent Het1-C(O)— on an alkyl group representing R14, is not greater than two, and in another embodiment it is not greater than one, and in another embodiment no oxo substituents are present on such a group Het1.
  • In one embodiment, a group Het3 occurring as a substituent on an alkyl group representing R14 is a saturated 4-membered to 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, and in another embodiment comprises one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom and is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in a group Het3 occurring as a substituent on an alkyl group representing R14 are chosen from the series consisting of nitrogen and oxygen, in another embodiment from the series consisting of oxygen and sulfur, in another embodiment they are nitrogen atoms, and in another embodiment they are oxygen atoms. In one embodiment, the number of substituents which are optionally present on a group Het3 occurring as a substituent on an alkyl group representing R14 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, the substituents which are optionally present on a group Het3 occurring as a substituent on an alkyl group representing R14 are chosen from the series consisting of fluorine and (C1-C4)-alkyl, in another embodiment from the series consisting of (C1-C4)-alkyl and oxo, in another embodiment they are (C1-C4)-alkyl substituents, and in another embodiment they are oxo substituents. In one embodiment, the number of oxo substituents which are optionally present on a group Het3 occurring as a substituent on an alkyl group representing R14, is not greater than two, and in another embodiment it is not greater than one.
  • In one embodiment, the substituents which are optionally present on an alkyl group representing R14 are chosen from the series consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Ar, Het1, Het3, H2N—C(O)—, (C1-C4)-alkyl-NH—C(O)—, di((C1-C4)-alkyl)N—C(O)— and Het1-C(O)—, in another embodiment from the series consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Het1, Het3, H2N—C(O)—, (C1-C4)-alkyl-NH—C(O)—, di((C1-C4)-alkyl)N—C(O)— and Het1-C(O)—, in another embodiment from the series consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Het1, Het3, di((C1-C4)-alkyl)N—C(O)— and Het1-C(O)—, in another embodiment from the series consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Het1 and Het3, in another embodiment from the series consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Ar, Het1 and Het3, in another embodiment from the series consisting of HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Ar, Het1, di((C1-C4)-alkyl)N—C(O)— and Het1-C(O)—, in another embodiment from the series consisting of HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Ar, di((C1-C4)-alkyl)N—C(O)— and Het1-C(O)—, in another embodiment from the series consisting of HO—, R16—O—, oxo, (C3-C7)-cycloalkyl and Ar, in another embodiment from the series consisting of HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, di((C1-C4)-alkyl)N—C(O)— and Het1-C(O)—, in another embodiment from the series consisting of HO—, oxo, (C3-C7)-cycloalkyl, Het1 and Het3, in another embodiment from the series consisting of HO—, R16—O—, oxo, (C3-C7)-cycloalkyl and Het3, in another embodiment from the series consisting of HO—, oxo, (C3-C7)-cycloalkyl and Het3, in another embodiment from the series consisting of HO—, oxo and (C3-C7)-cycloalkyl, in another embodiment from the series consisting of HO—, oxo and Het3, in another embodiment from the series consisting of HO— and oxo, in another embodiment from the series consisting of HO—, R16—O—, (C3-C7)-cycloalkyl and Het3, in another embodiment from the series consisting of HO—, (C3-C7)-cycloalkyl and Het3, in another embodiment from the series consisting of HO— and (C3-C7)-cycloalkyl, in another embodiment from the series consisting of HO— and Het3, in another embodiment they are HO— substituents, and in another embodiment they are oxo substituents. In one embodiment, the number of oxo substituents which are optionally present on an alkyl group representing R14, is not greater than two, and in another embodiment it is not greater than one. In one embodiment, halogen atoms occurring as substituents on an alkyl group representing R14, are chosen from the series consisting of fluorine and chlorine atoms, and in another embodiment they are fluorine atoms and, besides being substituted by an other substituents, in this latter embodiment an alkyl group representing R14 is thus optionally substituted by fluorine substituents as applies to alkyl groups in the compounds of the formula I in general.
  • Examples of groups which can represent R14, and from any one or more of which R14 is chosen in one embodiment of the invention, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, benzyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 2-hydroxy-butyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-butyl, 2-hydroxy-3-methyl-butyl, 2-hydroxy-2,3-dimethyl-butyl, 2-hydroxy-3,3-dimethyl-butyl, 2-ethyl-2-hydroxy-butyl, 2-hydroxy-2,3,3-trimethyl-butyl, 2-ethyl-2-hydroxy-3-methyl-butyl, 2-ethyl-2-hydroxy-3,3-dimethyl-butyl, 2-cyclopropyl-2-hydroxy-ethyl, 2-cyclopropyl-2-hydroxy-propyl, 2-cyclopropyl-2-hydroxy-butyl, 2-oxo-propyl, 2-oxo-butyl, 3-methyl-2-oxo-butyl, 3,3-dimethyl-2-oxo-butyl, 2-cyclopropyl-2-oxo-ethyl.
  • In case the optionally substituted alkyl group representing R14, including the examples of groups listed afore which can represent R14, contains a chiral carbon atom, the compound of the formula I can be present with respect to this carbon atom in any of it stereoisomeric forms, i.e. in R configuration or in S configuration, or in the form of a mixture of the stereoisomeric forms in any ratio, for example as a mixture of the two stereoisomeric forms in a molar ratio of 1:1, as applies to all chiral carbon atoms in the compounds of the formula I. In one embodiment of the invention, the compound of the formula I has at a chiral carbon atom in R14 pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater.
  • In one embodiment of the invention, the (C1-C6)-alkyl group representing the group R15 is a (C1-C4)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a methyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R15 is one or two, in another embodiment one. In one embodiment, the alkyl group representing R15 is unsubstituted. In one embodiment, the substituents which are optionally present on an alkyl group representing R15 are chosen from the series consisting of HO— and (C1-C4)-alkyl-O—.
  • In one embodiment of the invention, the (C1-C6)-alkyl group representing the group R16 is a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C2-C3)-alkyl group, in another embodiment an ethyl group, in another embodiment a methyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R16 is one or two, in another embodiment one. In one embodiment, an alkyl group representing R14 is unsubstituted, in another embodiment it is substituted by one or two identical or different substituents, in another embodiment it is substituted by one substituent. In one embodiment, the substituents which are optionally present on an alkyl group representing R15 are chosen from the series consisting of HO— and (C1-C4)-alkyl-O—, in another embodiment they are HO— substituents, in another embodiment they are (C1-C4)-alkyl-O— substituents, and in another embodiment they are (C1-C2)-alkyl-O— substituents.
  • In one embodiment of the invention, the group R30 is chosen from the series consisting of R31, (C3-C7)-cycloalkyl and Het3-CuH2u—, in another embodiment from the series consisting of (C3-C7)-cycloalkyl, R32—CuH2u— and Het3-CuH2u, in another embodiment from the series consisting of R32—CuH2u— and Het3-CuH2u—, in another embodiment R30 is R32—CuH2u—, and in another embodiment R30 is R31. In one embodiment, u is an integer chosen from the series consisting of 0, 1 and 2, in another embodiment from the series consisting of 0 and 1, in another embodiment from the series consisting of 1 and 2, in another embodiment u is 0, and in another embodiment u is 1. In one embodiment, R30 is R32—CuH2u— and u is 0, i.e., in this embodiment R30 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one, two or three identical or different ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the divalent alkanediyl group CuH2u is a linear group.
  • In one embodiment, the (C3-C7)-cycloalkyl group representing R30 is a (C3-C6)-cycloalkyl group, in another embodiment a (C5-C6)-cycloalkyl group, in another embodiment a cyclopropyl group. In one embodiment, a group Het3 occurring in R30 is a saturated 4-membered to 6-membered monocyclic heterocycle, in another embodiment a saturated 5-membered or 6-membered heterocycle, in another embodiment a saturated 6-membered heterocycle, which comprises one or two identical or different ring heteroatoms, and in another embodiment comprises one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom and is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in a group Het3 occurring in R30 are chosen from the series consisting of nitrogen and oxygen, in another embodiment from the series consisting of oxygen and sulfur, in another embodiment they are nitrogen atoms, and in another embodiment they are oxygen atoms. In one embodiment, the number of substituents which are optionally present on a group Het3 occurring in R30 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment a group Het3 occurring in R30 is unsubstituted. In one embodiment, the substituents which are optionally present on a group Het3 occurring in R30 are chosen from the series consisting of fluorine and (C1-C4)-alkyl, in another embodiment they are (C1-C4)-alkyl substituents.
  • In one embodiment of the invention, the (C1-C10)-alkyl group representing R31 is a (C1-C8)-alkyl group, in another embodiment a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a methyl group, in another embodiment a (C4-C8)-alkyl group, in another embodiment a (C5-C8)-alkyl group, wherein all these alkyl groups are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment of the invention, the number of optional substituents in an alkyl group representing R31 is one, two or three, in another embodiment one or two, in another embodiment one. In one embodiment, an alkyl group representing R31 is unsubstituted, and in another embodiment it is substituted by one, two or three, in another embodiment by one or two, in another embodiment by one substituent as indicated. In one embodiment, the optional substituents on an alkyl group representing R31 are chosen from the series consisting of halogen, (C3-C7)-cycloalkyl, (C1-C6)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C3-C7)-cycloalkyl and (C1-C6)-alkyl-O—, in another embodiment from the series consisting of halogen and (C3-C7)-cycloalkyl, and in another embodiment they are (C3-C7)-cycloalkyl substituents. In one embodiment, halogen atoms occurring as substituents on an alkyl group representing R31, are chosen from the series consisting of fluorine and chlorine atoms, and in another embodiment they are fluorine atoms and, besides being substituted by an other substituents, in this latter embodiment an alkyl group representing R31 is thus optionally substituted by fluorine substituents as applies to alkyl groups in the compounds of the formula I in general. In one embodiment, a (C3-C7)-cycloalkyl group occurring as a substituent on an alkyl group representing R30 is a (C3-C6)-cycloalkyl group, in another embodiment a (C5-C6)-cycloalkyl group, in another embodiment a cyclopropyl group.
  • In one embodiment of the invention, the group R32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, in another embodiment from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in an aromatic heterocycle representing R32 are chosen from the series consisting of nitrogen and sulfur, in another embodiment they are nitrogen atoms. In one embodiment, R32 is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle as defined, in another embodiment R32 is a 6-membered monocyclic heterocycle as defined, in another embodiment R32 is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment R32 is phenyl, and in another embodiment R32 is pyridinyl, all of which are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R32 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one.
  • In one embodiment, the substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R32, in particular on a phenyl group, are chosen from the series the series consisting of from halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, (C1-C4)-alkyl-NH—S(O)2—, di((C1-C4)-alkyl)N—S(O)2—, (C1-C6)-alkyl-NH—, di((C1-C6)-alkyl)N—, Het1, (C1-C4)-alkyl-C(O)—NH—, Ar—C(O)—NH—, (C1-C4)-alkyl-S(O)2—NH— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, (C1-C4)-alkyl-NH—S(O)2—, di((C1-C4)-alkyl)N—S(O)2—, (C1-C6)-alkyl-NH—, di((C1-C6)-alkyl)N—, Het1 and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, (C1-C6)-alkyl-NH—, di((C1-C6)-alkyl)N—, Het1 and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, R33, (C1-C6)-alkyl-O—, R33—O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, Het1 and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, R33, (C1-C6)-alkyl-O—, R33—O—, —O—CH2—O—, —O—CF2—O— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, R33, (C1-C6)-alkyl-O—, R33—O— and NC—,
  • in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, di((C1-C6)-alkyl)N—, Het1, (C1-C4)-alkyl-C(O)—NH—, Ar—C(O)—NH— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, di((C1-C6)-alkyl)N—, Het1 and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, di((C1-C6)-alkyl)N—, Het1 and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, di((C1-C6)-alkyl)N—, Het1 and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, R33, (C1-C6)-alkyl-O— and R33—O—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, R33 and (C1-C6)-alkyl-O—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl and R33, in another embodiment from the series consisting of halogen and (C1-C6)-alkyl. In one embodiment, in case that substituents from the series consisting of (C3-C7)-cycloalkyl, R33, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, Het1 and Ar—C(O)—NH— are present on a phenyl group and an aromatic heterocycle representing R32, not more than two such substituents, in another embodiment not more than one such substituent, are present, either without any other substituents or together with any other substituents.
  • In one embodiment, a (C1-C6)-alkyl group occurring in a substituent on a phenyl group and an aromatic heterocycle representing R32 is a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a methyl group. In one embodiment, a (C3-C7)-cycloalkyl group occurring as a substituent on a phenyl group and an aromatic heterocycle representing R32 is a (C3-C6)-cycloalkyl group, in another embodiment a (C3-C5)-cycloalkyl group, in another embodiment a (C3-C4)-cycloalkyl group, in another embodiment it is a cyclopropyl group. In one embodiment, a group Ar occurring in a substituent on a phenyl group and an aromatic heterocycle representing R32 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, chosen from the series consisting of nitrogen, oxygen and sulfur, which is bonded via a ring carbon atom, and in another embodiment it is a phenyl group, which groups all are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of optional substituents on a group Ar occurring in a substituent on a phenyl group and an aromatic heterocycle representing R32 is one or two, in another embodiment one, and the optional substituents are chosen from the series consisting of halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O—, (C1-C4)-alkyl-S(O)m— and NC—, in another embodiment from the series consisting of halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O—, in another embodiment from the series consisting of halogen and (C1-C4)-alkyl, and in another embodiment such a group Ar is unsubstituted.
  • In one embodiment, a group Het1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R32 is a saturated or unsaturated 4-membered to 6-membered monocyclic heterocycle, in another embodiment a 5-membered or 6-membered heterocycle, which comprises a ring nitrogen atom via which Het1 is bonded and optionally one or two further ring heteroatoms, in another embodiment one further ring heteroatom, which are chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, a group Het1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R32 does not comprise any further ring heteroatom besides the ring nitrogen atom via which Het1 is bonded. In one embodiment, a group Het1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R32 is saturated, in another embodiment it is unsaturated. In one embodiment, the number of substituents which are optionally present on a group Het1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R32 is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het1 is unsubstituted. In one embodiment, the substituents which are optionally present on a group Het1 occurring as a substituent on a phenyl group or an aromatic heterocycle representing R32 are chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O— and oxo, in another embodiment from the series consisting of fluorine, (C1-C4)-alkyl, HO— and oxo, in another embodiment from the series consisting of fluorine, (C1-C4)-alkyl and oxo, and in another embodiment they are (C1-C4)-alkyl substituents.
  • Examples of groups R32 from any one or more of which R32 is chosen in one embodiment of the invention, are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-phenyl, 3,4-dichloro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-methyl-phenyl (p-tolyl), 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 3-isopropyl-phenyl, 3-tert-butyl-phenyl, 4-tert-butyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 5-chloro-2-fluoro-3-methyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 5-chloro-2-trifluoromethyl-phenyl, 5-chloro-3-trifluoromethyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3-ethoxy-phenyl, 3-propoxy-phenyl, 3-isopropoxy-phenyl, 4-tert-butoxy-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-(2,2,2-trifluoroethoxy)-phenyl, 5-chloro-2-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 5-fluoro-3-isopropoxy-phenyl, 2-fluoro-3-trifluoromethoxy-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 3-methoxy-5-trifluoromethyl-phenyl, 2,3-methylenedioxy-phenyl, 2,3-difluoromethylenedioxy-phenyl, 3,4-methylenedioxy-phenyl, 3,4-difluoromethylenedioxy-phenyl, 3-methylsulfanyl-phenyl, 3-ethylsulfanyl-phenyl, 3-trifluoromethylsulfanyl-phenyl, 3-methanesulfonyl-phenyl, 3-ethanesulfonyl-phenyl, 3-sulfamoyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, thiophen-2-yl, thiophen-3-yl, 3-chloro-thiophen-2-yl, 4-chloro-thiophen-2-yl, 5-chloro-thiophen-2-yl, 4,5-dichloro-thiophen-2-yl, 5-chloro-thiophen-3-yl, 2,5-dichloro-thiophen-3-yl, 4-methyl-thiophen-2-yl, 5-methyl-thiophen-3-yl, 4,5-dimethyl-thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-chloro-pyridin-3-yl, 5-chloro-pyridin-2-yl, 6-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl, 2,6-dichloro-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-chloro-6-methoxy-pyridin-3-yl.
  • In one embodiment of the invention, the group R33 is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which is chosen from the series consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the ring heteroatoms in an aromatic heterocycle representing R33 are chosen from the series consisting of nitrogen and sulfur, in another embodiment they are nitrogen atoms. In one embodiment, R33 is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle as defined, in another embodiment from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment R33 is a 6-membered monocyclic heterocycle as defined, in another embodiment it is an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment R33 is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment R33 is phenyl, and in another embodiment R33 is pyridinyl, all of which are optionally substituted by one or more identical or different substituents as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R33 is one, two or three, in another embodiment one or two, in another embodiment one.
  • In one embodiment, the substituents which are optionally present on a phenyl group and an aromatic heterocycle representing R33, are chosen from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O—, H2N—S(O)2—, di((C1-C4)-alkyl)N—S(O)2— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O—, H2N—S(O)2—, di((C1-C4)-alkyl)N—S(O)2— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O— and NC—, are chosen from the series the series consisting of halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O—, (C1-C4)-alkyl-S(O)m— and NC—, in another embodiment from the series consisting of halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O—, in another embodiment from the series consisting of halogen and (C1-C4)-alkyl. In one embodiment, a (C1-C6)-alkyl group occurring in a substituent on a phenyl group and an aromatic heterocycle representing R33 is a (C1-C4)-alkyl group, in another embodiment a (C1-C3)-alkyl group, in another embodiment a (C1-C2)-alkyl group, in another embodiment a methyl group. In one embodiment, a (C3-C7)-cycloalkyl group occurring as a substituent on a phenyl group and an aromatic heterocycle representing R32 is a (C3-C6)-cycloalkyl group, in another embodiment a (C3-C6)-cycloalkyl group, in another embodiment a (C3-C4)-cycloalkyl group, in another embodiment it is a cyclopropyl group.
  • In one embodiment of the invention, the group R40 is chosen from the series consisting of hydrogen and (C1-C2)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R40 is hydrogen. In case R30 and R40 are different and the carbon atom carrying R30 and R40 thus is chiral, in one embodiment of the invention the compound of the formula I has at this carbon atom pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater. In case R30 is R32—CuH2u— and u is 0, i.e. R30 is phenyl or an aromatic heterocycle as defined, R40 is hydrogen and R50 is hydrogen, in one embodiment of the invention the compound of the formula I has at the carbon atom carrying R30 and R40 pure S configuration, or essentially pure S configuration, for example with a molar ratio of S configuration to R configuration of 99:1 or greater.
  • In case R30 and R40 together are a divalent group (CH2)x, the two groups R30 and R40 together with the carbon atom carrying them form a cycloalkane ring chosen from cyclopropane, cyclobutane, cyclopentane and cyclohexane, which carries the moieties —C(O)—NH and —C(R50)(R60)-G depicted in formula I on the same ring carbon atom. In one embodiment of the invention, the number of (C1-C4)-alkyl substituents which are optionally present on the group (CH2)x, is one, two, three or four, in another embodiment one or two, and in another embodiment no alkyl substituents are present on the group (CH2)x. In one embodiment, a (C1-C4)-alkyl group occurring as a substituent on the group (CH2)x is a methyl group. In one embodiment, the integer x is chosen from the series consisting of 2, 4 and 5, in another embodiment from 4 and 5, in another embodiment x is 2, and in another embodiment x is 4. In one embodiment of the invention, R30 and R40 together cannot be (CH2)x, and in this embodiment R30 and R40 thus only have their other meanings as defined.
  • In one embodiment of the invention, the group R50 is chosen from the series consisting of hydrogen, (C1-C4)-alkyl and HO—, in another embodiment from the series consisting of hydrogen and (C1-C4)-alkyl, in another embodiment from the series consisting of hydrogen and (C1-C2)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, in another embodiment from the series consisting of hydrogen and HO—, and in another embodiment R50 is hydrogen.
  • In one embodiment of the invention, the group R60 is chosen from the series consisting of hydrogen and (C1-C4)-alkyl, in another embodiment from the series consisting of hydrogen and (C1-C3)-alkyl, in another embodiment from the series consisting of hydrogen and (C1-C2)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R60 is hydrogen.
  • In one embodiment of the invention, R50 and R60 both are hydrogen. In case R50 and R60 are different and the carbon atom carrying R50 and R60 thus is chiral, in one embodiment of the invention the compound of the formula I has at this carbon atom pure stereochemical configuration, either R configuration or S configuration, or essentially pure stereochemical configuration, for example with a molar ratio of the two configurations of 99:1 or greater.
  • In case R50 and R60 together are a divalent group (CH2)y, the two groups R50 and R60 together with the carbon atom carrying them form a cycloalkane ring chosen from cyclopropane, cyclobutane, cyclopentane and cyclohexane, which carries the moieties and G depicted in formula I on the same ring carbon atom. In one embodiment of the invention, the number of (C1-C4)-alkyl substituents which are optionally present on the group (CH2)y, is one, two, three or four, in another embodiment one or two, and in another embodiment no alkyl substituents are present on the group (CH2)y. In one embodiment, a (C1-C4)-alkyl group occurring as a substituent on the group (CH2)y is a methyl group. In one embodiment, the integer y is chosen from the series consisting of 2, 4 and 5, in another embodiment from 4 and 5, in another embodiment y is 2, and in another embodiment y is 4. In one embodiment of the invention, R50 and R60 together cannot be (CH2)y, and in this embodiment R50 and R60 thus only have their other meanings as defined. In one embodiment of the invention, R50 and R60 together cannot be (CH2)y if simultaneously R30 and R40 together are (CH2)x.
  • In one embodiment of the invention, the group R71 is chosen from the series consisting of hydrogen and (C1-C6)-alkyl, in another embodiment from the series consisting of hydrogen and (C1-C4)-alkyl, in another embodiment from the series consisting of hydrogen and (C1-C3)-alkyl, in another embodiment from the series consisting of hydrogen and (C1-C2)-alkyl, in another embodiment R71 is hydrogen, in another embodiment R71 is (C1-C6)-alkyl, in another embodiment R71 is (C1-C4)-alkyl, in another embodiment R71 is (C1-C3)-alkyl, and in another embodiment R71 is (C1-C2)-alkyl, wherein all these alkyl groups are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on an alkyl group representing R71 is one or two, in another embodiment it is one, in another embodiment an alkyl group representing R71 is unsubstituted. In one embodiment, substituents which are optionally present on an alkyl group representing R71 are (C1-C6)-alkyl-O-substituents, in another embodiment (C1-C4)-alkyl-O— substituents, in another embodiment (C1-C3)-alkyl-O— substituents, in another embodiment (C1-C6)-alkyl-C(O)—O— substituents, in another embodiment (C1-C4)-alkyl-C(O)—O— substituents, in another embodiment (C1-C3)-alkyl-C(O)—O— substituents.
  • In one embodiment the group R72 is chosen from the series consisting of hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl —CH2—(CH2)b—(C3-C6)-cycloalkyl and —(CH2)b-Het4, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—, NC—, N((C1-C4)-alkyl)2 and b is 0, 1 or 2 and the group R73 is chosen from the series consisting hydrogen, (C1-C6)-alkyl.
  • In another embodiment the groups R72 and R73 together with the nitrogen atom to which they are bonded form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—.
  • In another embodiment the group R72 is chosen from the series consisting of hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, Het4 and —CH2-Het4, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—, NC—, N((C1-C4)-alkyl)2 and the group R73 is chosen from the series consisting hydrogen, (C1-C6)-alkyl.
  • In another embodiment the groups R72 and R73 together with the nitrogen atom to which they are bonded form a saturated 5-membered to 6-membered monocyclic heterocycle, which contain optionally one further ring heteroatom chosen from the series consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—.
  • In one embodiment the group R72 is chosen from the series consisting of hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl and —CH2-Het4, where alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, HO—, HOOC—, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—, NC—, N((C1-C4)-alkyl)2 and the group R73 is chosen from the series consisting hydrogen and (C1-C6)-alkyl.
  • In another embodiment the groups R72 and R73 together with the nitrogen atom to which they are bonded form a saturated 5-membered to 6-membered monocyclic heterocycle, which contain no further ring heteroatoms, which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—.
  • In one embodiment the group R72 is chosen from the series consisting of hydrogen, 2,2-dimethyl-butane-3yl, 2,2-dimethyl-propane-3yl, pentan-3yl, propane-2yl, 2-methyl-propane-2yl, butane-1yl, butane-2yl, 2-methyl-butane-3yl, 2-methyl-butane-2-yl, —CH2CHF2, —CHCF3, CH2CN, —CH2CH2OCH3, —CH(CH2OH)CH(CH3)2, —CH2C(CH3)2—CH2OH, CH(C2H5)CH2OCH3, CH2CH2CH2N(CH3)2, cyclopropane, cyclobutane, cyclopentane, cyclohexane and —CH2-Het4 and the group R73 is hydrogen.
  • In another embodiment the groups R72 and R73 together with the nitrogen atom to which they are bonded form pyrrolidine, which is optionally substituted by HO—.
  • In another embodiment the group R72 is chosen from the series consisting of hydrogen, (C1-C6)-alkyl, where alkyl is substituted by one or more times by HO— and the group R73 is hydrogen.
  • In one embodiment of the invention, the groups R72 and R73 are independently of each other chosen from the series consisting of hydrogen and (C1-C2)-alkyl, in another embodiment from the series consisting of hydrogen and methyl. In one embodiment, one of the groups R72 and R73 is hydrogen and the other is chosen from the series consisting of hydrogen and (C1-C4)-alkyl, in another embodiment from the series consisting of hydrogen and (C1-C2)-alkyl, in another embodiment from the series consisting of hydrogen an methyl, and in another embodiment both groups R72 and R73 are hydrogen.
  • In one embodiment of the invention the group Het4, independently of each other group Het4, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O—, oxo and NC—; In another embodiment the group Het4, independently of each other group Het4, is a saturated or unsaturated 5-membered to 6-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O—, oxo and NC—;
  • In another embodiment the group Het4, independently of each other group Het4, is a unsaturated 5-membered to 6-membered monocyclic heterocycle which comprises one to four ring heteroatoms chosen from the series consisting of nitrogen, oxygen and sulfur which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O— and NC—;
  • In another embodiment the group Het4, independently of each other group Het4, is selected from 1,2-oxadiazolyl, tetrazlolyl, pyrazolyl, furanyl, pyridinyl, pyriminyl, which is optionally substituted by methyl.
  • In one embodiment of the invention, a group Ar in any occurrence in the compounds of the formula I, independently of each other group Ar, is chosen from the series consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle which comprises one or two identical or different ring heteroatoms, in another embodiment one ring heteroatom, which is chosen from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom, in another embodiment Ar is chosen from the series consisting of phenyl and an aromatic 6-membered heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, in another embodiment Ar is chosen from the series consisting of phenyl, thiophenyl and pyridinyl, in another embodiment from the series consisting of phenyl and thiophenyl, in another embodiment from the series consisting of phenyl and pyridinyl, in another embodiment a group Ar is phenyl, and in another embodiment a group Ar is pyridinyl, wherein the phenyl and all heterocycles are optionally substituted as indicated with respect to the compounds of formula I in general or in any embodiment specified above or below. In one embodiment, the number of substituents which are optionally present on a group Ar, independently of each other group Ar, is one, two, three or four, in another embodiment one, two or three, in another embodiment one or two, in another embodiment one, and in another embodiment a group Ar is unsubstituted.
  • In one embodiment, in case that substituents from the series consisting of —CH═CH—CH═CH—, —O—CH2—CH2—O—, —N((C1-C3)-alkyl)-CH═CH—, —O—CH2—O— and —O—CF2—O— are present on a group Ar which is phenyl, not more than two such substituents, in another embodiment not more than one such substituent, are present, either without any other substituents or together with any other substituents. In one embodiment, the substituents which are optionally present on a group Ar, independently of each other group Ar, are chosen from the series consisting of halogen, (C1-C6)-alkyl, HO—(C1-C6)-alkyl, Het4, —(CH2)x-phenyl, (C1-C6)-alkyl-O—, (C3-C7)-cycloalkyl-(CH2)x—O—, —CF3, —CO—(C1-C6)-alkyl, —NR12R13, Het2, —CO—NR12R13, CO-Het2, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2— and NC—; in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O— and NC—, in another embodiment from the series consisting of halogen, (C1-C6)-alkyl and (C1-C6)-alkyl-O—, in another embodiment from the series consisting of halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O—, in another embodiment from the series consisting of halogen and (C1-C4)-alkyl.
  • A subject of the invention are all compounds of the formula I wherein any one or more structural elements such as groups, substituents and numbers are defined as in any of the specified embodiments or definitions of the elements or have one or more of the specific meanings which are mentioned herein as examples of elements, wherein all combinations of one or more specified embodiments and/or definitions and/or specific meanings of the elements are a subject of the present invention. Also with respect to all such compounds of the formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratios, and their physiologically acceptable salts, and the physiologically acceptable solvates of any of them, are a subject of the present invention.
  • As an example of compounds of the invention which with respect to any structural elements are defined as in specified embodiments of the invention or definitions of such elements, compounds of the formula I may be mentioned wherein
  • G is chosen from the series consisting of R71—O—C(O)— and R72—N(R73)—C(O)—;
  • R30 is R32—CuH2u—, wherein u is an integer chosen from the series consisting of 0 and 1;
  • R32 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, HO—, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, di((C1-C6)-alkyl)N—, Het1, (C1-C4)-alkyl-C(O)—NH—, Ar—C(O)—NH— and NC—;
  • R33 is chosen from the series consisting of phenyl and an aromatic 6-membered monocyclic heterocycle which comprises one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle all are optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O —, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, di((C1-C4)-alkyl)N—S(O)2— and NC—; R40 is hydrogen.
  • As another such example of compounds of the invention which with respect to any structural elements are defined as in specified embodiments of the invention or definitions of such elements, compounds of the formula I may be mentioned wherein
    • G is R71—O—C(O)—;
  • R30 is R32—CuH2u—, wherein u is 0;
    R32 is chosen from the series consisting of phenyl, wherein the phenyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, R33, HO—, (C1-C6)-alkyl-O—, R33—O—, R33—(C1-C4)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, di((C1-C6)-alkyl)N—, Het1, (C1-C4)-alkyl-C(O)—NH—, Ar—C(O)—NH— and NC—;
    R33 is chosen from the series consisting of phenyl, wherein the phenyl is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, di((C1-C4)-alkyl)N—S(O)2— and NC—;
    R40 is hydrogen.
  • As another such example of compounds of the invention which with respect to any structural elements are defined as in specified embodiments of the invention or definitions of such elements, compounds of the formula I may be mentioned wherein
  • R50 is hydrogen;
    R60 is hydrogen.
  • As another such example of compounds of the invention which with respect to any structural elements are defined as in specified embodiments of the invention or definitions of such elements, compounds of the formula I may be mentioned wherein
  • formula I is selected from the series of subformulae I-1 to I-7
  • Figure US20140135328A1-20140515-C00005
  • As another such example of compounds of the invention which with respect to any structural elements are defined as in specified embodiments of the invention or definitions of such elements, compounds of the formula I-1
  • Figure US20140135328A1-20140515-C00006
  • wherein
    R2 is Ar—CsH2s—, wherein s is an integer chosen from the series consisting of 0;
    R3 is chosen from the series consisting of hydrogen, halogen, R11—O—, HO—, (C1-C6)-alkyl and (C1-C6)-alkyl-O—; preferred HO— and (C1-C6)-alkyl;
    R4 is hydrogen;
    R10 is hydrogen;
    As another such example of compounds of the invention which with respect to any structural elements are defined as in specified embodiments of the invention or definitions of such elements, compounds of the formula I-1
  • Figure US20140135328A1-20140515-C00007
  • wherein
    R1 is hydrogen;
    R3 is chosen from the series consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-S(O)m—, Phenyl CsH2s—(O)t—, Het4-(O)t—, —NR12R13, Het2, R11—O—, R12—N(R13)—C(O)—O— and Het2-C(O)—O— and NC—, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1;
  • R4 is hydrogen;
  • R10 is chosen from the series consisting hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, HO—, —NR12R13, Het2, phenyl-CsH2s—(O)t—, wherein s is an integer chosen from the series consisting of 0, 1, 2 and 3 and wherein t is an integer chosen from the series consisting of 0 and 1;
  • A subject of the invention also is a compound of the formula I which is chosen from any of the specific compounds of the formula I which are disclosed herein, or is any one of the specific compounds of the formula I which are disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a specific salt, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein the compound of the formula I is a subject of the invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio. For example, a subject of the invention is a compound of the formula I which is chosen from
    • (S)-3-[(5-Methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-(2,4-Dichloro-phenyl)-3-[(5-methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-[(6-Chloro-5-methoxy-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[3-(4,6-Dimethoxy-pyrimidin-2-yloxy)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[4-(Pyrimidin-2-ylsulfanyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(5-Phenyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[5-(2-Chloro-phenyl)-pyridine-3-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[5-(2,3-Dichloro-phenyl)-pyridine-3-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[5-(2,3-Dimethyl-phenyl)-pyridine-3-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-o-Tolyl-3-[(6-m-tolyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,3-Difluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,5-Difluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Fluoro-2-methyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,3-Dimethyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(5-Fluoro-2-methyl-phenyl)-pyridine-2-carbonyl]amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Methoxy-4-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Chloro-2-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-5-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-5-methyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-[(5-Methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-3-p-tolyl-propionic acid
    • (S)-3-[(5-Methoxy-6-o-tolyl-pyridine-2-carbonyl)-amino]-3-p-tolyl-propionic acid
    • (S)-3-{[5-Methoxy-6-(2-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(3-Fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[5-Methoxy-6-(2-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2,4-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2,3-Dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2-Chloro-5-trifluoromethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(3-Fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2-Chloro-5-trifluoromethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2,3-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2,5-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2,5-Dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(3,5-Dimethyl-isoxazol-4-yl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(4-Fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2,3-Dimethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3[(3,2′-Dimethoxy-[2,3′]bipyridinyl-6-carbonyl)-amino]-3-p-tolyl-propionic acid
    • (S)-3-{[6-(5-Fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(4-Fluoro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(5-Fluoro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-5-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(3-Chloro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(3-Fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(5-Chloro-2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-[(5-methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-{[6-(2,4-Dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-[(5-methoxy-6-o-tolyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-{[5-methoxy-6-(2-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-{[5-methoxy-6-(2-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-{[6-(2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(2,4-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2,3-Dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2,3-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2,5-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(4-Fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(3,5-Dimethyl-isoxazol-4-yl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2,3-Dimethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-[(3,2′-Dimethoxy-[2,3]bipyridinyl-6-carbonyl)-amino]-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(5-Fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(4-Fluoro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(5-Fluoro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2-Fluoro-5-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(3-Chloro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(5-Chloro-2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(3-Chloro-2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-{[5-methoxy-6-(2-methyl-furan-3-yl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(2-Chloro-3-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(5-methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2,4-dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(4-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[5-Methoxy-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,4-Dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-[(5-Methoxy-6-p-tolyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[5-Methoxy-6-(2-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-[(5-Methoxy-6-m-tolyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(3,4-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,5-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,5-Dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(3,5-Dimethyl-isoxazol-4-yl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,3-Dimethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,4-Dimethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Fluoro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Chloro-5-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(6-methoxy-5-o-tolyl-pyridine-3-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[5-methoxy-6-(2-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(5-methoxy-6-m-tolyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2-chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2,4-difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2,3-dichloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2,3-difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2,5-difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(4-fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2,3-dimethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(3,2′-dimethoxy-[2,3]bipyridinyl-6-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(5-fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(4-fluoro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(4-Chloro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-chloro-phenyl)-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(5-fluoro-2-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2-fluoro-5-trifluoromethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[5-Methoxy-6-(2-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,4-Difluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-[(3,2′-Dimethoxy-[2,3′]bipyridinyl-6-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(3′-Fluoro-3-methoxy-[2,4]bipyridinyl-6-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[5-Methoxy-6-(2-methyl-furan-3-yl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Cyano-2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2-fluoro-5-methoxy-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2-fluoro-5-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(3-Chloro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-chloro-phenyl)-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(3-fluoro-2-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(5-Chloro-2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-chloro-phenyl)-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(3′-fluoro-3-methoxy-[2,4]bipyridinyl-6-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(5-methoxy-6-pyrazin-2-yl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-{[6-(3-Chloro-2-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-chloro-phenyl)-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[5-methoxy-6-(2-methyl-furan-3-yl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(2-Chloro-3-fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-chloro-phenyl)-propionic acid
    • (S)-3-{[6-(2-Chloro-3-methyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-chloro-phenyl)-propionic acid
    • 3-Biphenyl-4-yl-3-[(6-chloro-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-[(6-Chloro-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • 3-Biphenyl-4-yl-3-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-phenyl-propionic acid
    • (S)-3-(3-Fluoro-phenyl)-3-{[6-(2-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-{[6-(2-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(4-Fluoro-phenyl)-3-{[6-(2-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • 3-(2-Chloro-phenyl)-3-[(6-methoxy-quinoline-2-carbonyl)-amino]-propionic acid
    • (S)-3-[(6-Methoxy-biphenyl-3-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-m-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-(4-methoxy-phenyl)-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-(4-fluoro-phenyl)-propionic acid
    • (S)-3-(3-Chloro-phenyl)-3-{[6-(2-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(4-Chloro-phenyl)-3-{[6-(2-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(4-Chloro-phenyl)-3-{[6-(2-chloro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(3-Chloro-phenyl)-3-{[6-(2-chloro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • 3-(2-Chloro-phenyl)-3-{[6-(2-chloro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-(3-trifluoromethyl-phenyl)-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-(2,4-dichloro-phenyl)-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-(4-trifluoromethyl-phenyl)-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-(3-trifluoromethyl-phenyl)-propionic acid
    • (S)-3-{[6-Bromo-5-(3,3-dimethyl-2-oxo-butoxy)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid.
  • For example, also a subject of the invention is a compound of the formula I which is chosen from
    • (S)-3-[(5-Methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,3-Dimethyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(5-Fluoro-2-methyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-o-Tolyl-3-[(6-m-tolyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-({6-[3-(1-Hydroxy-1-methyl-ethyl)-phenyl]-pyridine-2-carbonyl}-amino)-3-o-tolyl-propionic acid
    • (S)-3-(2,4-Dichloro-phenyl)-3-[(5-methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-[(2,6-Dimethoxy-pyrimidine-4-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(5-Phenyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[3-(4,6-Dimethoxy-pyrimidin-2-yloxy)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[4-(Pyrimidin-2-ylsulfanyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[5-(2,3-Dichloro-phenyl)-pyridine-3-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[5-(2,3-Dimethyl-phenyl)-pyridine-3-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[5-(2-Chloro-phenyl)-pyridine-3-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2,3-Difluoro-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-5-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Fluoro-5-methyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Methoxy-4-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-({5-Methoxy-6-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-pyridine-2-carbonyl}-amino)-3-o-tolyl-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(5-methoxy-6-naphthalen-2-yl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(5-methoxy-6-pyrazin-2-yl-pyridine-2-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-[(6-methoxy-5-naphthalen-2yl-pyridine-3-carbonyl)-amino]-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[5-methoxy-6-(2-methyl-furan-3-yl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2,3-dimethyl-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Chloro-phenyl)-3-{[6-(2-chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-{[5-methoxy-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-(2-Fluoro-phenyl)-3-{[5-methoxy-6-(1-methyl-1H-indol-5-yl)-pyridine-2-carbonyl]-amino}-propionic acid
    • (S)-3-[(5-Methoxy-6-m-tolyl-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-{[6-(2-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(3,5-Dimethyl-isoxazol-4-yl-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
    • (S)-3-{[6-(4-Chloro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-p-tolyl-propionic acid
    • (S)-3-{[6-(5-Acetyl-thiophen-2-yl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-(2-chloro-phenyl)-propionic acid
    • (S)-3-{[6-(2-Fluoro-phenyl)-5-methoxy-pyridine-2-carbonyl]-amino}-3-o-tolyl-propionic acid
      or which is any one of these compounds, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, wherein the compound of the formula I is a subject of the invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, unless a specific stereoisomeric form is specified with respect to any carbon atoms in the respective compound.
  • Another subject of the present invention are processes for the preparation of the compounds of the formula I which are outlined below and by which the compounds are obtainable. For example, the preparation of the compounds of the formula I can be carried out by reacting a compound of the formula II with a compound of the formula III with formation of an amide bond. Various synthetic methods for the formation of the amide bond are described in C. A. G. N. Montalbetti et al., Tetrahedron 61 (2005), 10827-10852, for example.
  • In general the compounds described in this patent are synthesized according to the general scheme:
  • Figure US20140135328A1-20140515-C00008
  • The formation of the amide bond between the carboxylic acid and the β-amino-acid can be done by the use of coupling agents well known to a person skilled in the art and described for example in Tetrahedron (2005), 61(46), 10827-10852. As alternatives instead of a carboxylic acid a carboxylic acid chloride and instead of the free β-amino acid a β-amino acid ester, especially methyl- or ethylester, may be used.
  • The β-amino-acids used within this work are either commercially available or prepared by methods described for example in JACS 1935, 1279 or by Rhodionow in Chem. Abstr. 1953, 1051. The Rhodionow scheme is depicted below:
  • Figure US20140135328A1-20140515-C00009
  • Enantiopure β-amino acids can either be obtained commercially or prepared from the racemic material by procedures described in Bioscience, Biotechnology and Biochemistry, 2006, 1941.
  • A general procedure for the coupling process using heterocyclic carboxylic acids is described below. The used carboxylic acids are commercially available.
    • Procedure A
  • 0.25 mmol of the carboxylic acid is weighed into a reaction vial, 1.25 mmol N-ethyl morpholine in 1 ml DMF is added, followed by 0.245 mmol TOTU in 0.5 ml DMF. The mixture is allowed to react for 30 min at RT. 0.275 mmol of the amino acid suspended in 0.5 ml DMF is added, the vial is closed with a screw cap and shaken over night at RT. 0.2 ml TFA is added, the solution is filtered through syringe filters and directly submitted to prep HPLC.
  • Yield of the products: Between 5% and 80%
  • Another general procedure consists of the synthesis of amino acid derivatives with a functional group suitable for a subsequent Suzuki reaction as shown below.
  • Figure US20140135328A1-20140515-C00010
  • The synthetic steps are described below in more detail:
    • Step 1: Esterification of β-amino acids Synthesis of (S)-3-Amino-3-(2-fluoro-phenyl)-propionic acid ethyl ester
  • 5.0 g (27, 3 mmol) (S)-3-Amino-3-(2-fluorophenyl)-propionic acid are suspended in 27 ml Methyl-THF and 16 ml ethanol and heated to 80° C.
  • 2.45 ml (4.02; 33.8 mml; 1.24 eq) SOCl2 are added and the resulting mixture is stirred for 2.5 h at 80° C. The mixture is allowed to reach RT and stirred overnight. The solvent is evaporated in vacuo and 9.2 g of crude material is obtained, which is washed several times with diisopropylether to obtain 6.34 g of pure material
  • (Yield: 94%).
  • According to this procedure the following derivatives have been prepared:
    • (S)-3-Amino-3-(2-chloro-phenyl)-propionic acid ethyl ester
    • (S)-3-Amino-3-o-tolyl-propionic acid ethyl ester
    • (S)-3-Amino-3-p-tolyl-propionic acid ethyl ester
    Step 2: Coupling of products from 1 to heterocyclic carboxylic acids substituted with chlorine or bromine atoms: Synthesis of (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid ethyl ester
  • 4.87 g (21 mmol) 6-Bromo-5-methoxy-pyridine-2-carboxylic acid and 4.17 g (25.2 mmol, 1.2 eq) CDI are suspended in 54 ml Me-THF and heated to 50° C. After stirring for 3.5 h at this temperature the mixture is cooled to 0° C. in an ice bath and 3.39 ml (24.2, 1.15 eq) triethyl-amine is added. After that 6.1 g (23.1 mmol, 1.1 eq) of (S)-3-Amino-3-(2-chloro-phenyl)-propionic acid ethyl ester are added within 20 minutes and the resulting mixture is allowed to reach RT and stirred overnight.
  • 50 ml water is added, the phases are separated and the organic phase is washed several times with 50 ml of saturated NaHCO3 solution followed by 50 ml of 1N HCl solution. The organic phase is evaporated in vacuo and 8.43 g of product are obtained. Yield: 89%.
  • According to this procedure the following derivatives have been prepared:
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid ethyl ester
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-p-tolyl-propionic acid ethyl ester
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-(2-fluoro-phenyl)-propionic acid ethyl ester
    • (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-o-tolyl-propionic acid ethyl ester
    • (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid ethyl ester
    • (S)-3-[(5-Bromo-pyridine-3-carbonyl)-amino]-3-o-tolyl-propionic acid ethyl ester
    • (S)-3-[(2-Chloro-6-methoxy-pyridine-4-carbonyl)-amino]-3-o-tolyl-propionic acid ethyl ester
    • (S)-3-[(2-Chloro-pyridine-4-carbonyl)-amino]-3-o-tolyl-propionic acid ethyl ester
    • (S)-3-[(6-Chloro-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid ethyl ester
    Step 3: Hydrolysis of products from step 2: Synthesis of (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid
  • 8.03 g (20.21 mmol) (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid ethyl ester are dissolved in 15.2 ml (30.32 mmol, 1.5 eq) 2N NaOH solution and stirred at 50° C. for 9 hours. The resulting mixture is stirred overnight at RT.
  • 105 ml water and 30 ml isopropanol are added and the pH is adjusted to pH=3.0 with 2N HCl. The precipitate is separated and dried in vacuo to deliver 3.74 g of product (Yield: 50%).
  • According to this procedure the following derivatives have been prepared:
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-p-tolyl-propionic acid
    • (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-(2-fluoro-phenyl)-propionic acid
    • (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(5-Bromo-pyridine-3-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(2-Chloro-6-methoxy-pyridine-4-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(2-Chloro-pyridine-4-carbonyl)-amino]-3-o-tolyl-propionic acid
    • (S)-3-[(6-Chloro-pyridine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
    Procedures for Suzuki Couplings: General Procedure B Synthesis of (S)-3-(2-Fluoro-phenyl)-3-[(5-methoxy-6-phenyl-pyridine-2-carbonyl)-amino]-propionic acid (Example 263) 50 mg (0.12 mmol) of (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-(2-fluoro-phenyl)-propionic acid are dissolved in 3 ml of DMF, 120 mg (0.16 mmol, 1.35 eq) phenylboronic acid, 10 mg of bis(triphenylphosphine)palladium(II)chloride as catalyst and 1 ml of 1N Na2CO3 solution are added and the resulting mixture is heated to 100° C. for 6 hours. The mixture is filtrated via a pad of celite and subjected to preparative HPLC chromatography to yield 15 mg (31%) of product. General Procedure C Synthesis of (S)-3-(2-Chloro-phenyl)-3-[(6-methoxy-5-phenyl-pyridine-3-carbonyl)-amino]-propionic acid (Example 353)
  • To a solution of 50 mg (0.13 mmol) of (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid in 3 ml of DMF are added: 25 mg (0.21 mmol, 1,5 eq) phenylboronic acid, 60 mg Na2CO3 (0.56 mmol, 4.2 eq) and 10 mg (0.13 eq) DI-MICRO-CHLOROBIS[2-[(DIMETHYLAMINO)METHYL]PHENYL-C,N]DIPAL as catalyst. After the addition of 1 ml of water the resulting mixture is heated to 100° C. for 6 hours, the reaction is filtered via a pad of celite and the resulting solution subjected to preparative HPLC chromatography yielding 16 mg of product (Yield: 29%).
  • The groups A, D, E, L, G, R10, R30, R40, R50 and R60 in the compounds of the formulae II and III are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group which is later converted into the final group. The group J in the compounds of the formula II can be HO— (hydroxy), i.e. the compound of the formula II can thus be a carboxylic acid, or another group which can be replaced by the group NH in the compound of the formula III in a substitution reaction, for example an aryloxy group such as optionally substituted phenoxy or an alkyloxy group such as a (C1-C4)-alkyl-O— group, for example a (C1-C3)-alkyl-O— group like methoxy or ethoxy, or halogen, for example chlorine or bromine, and the compound of the formula II can thus be a reactive ester like an aryl ester or alkyl ester, for example a methyl ester or ethyl ester, or an acid halide, for example an acid chloride or acid bromide, of the respective carboxylic acid. The compounds of the formulae II and III can also be employed, and the compounds of the formula I obtained, in the form of a salt, for example an acid addition salt such as an hydrohalide, for example a hydrochloride, of the compound of the formula III and/or an alkaline metal salt, for example a sodium salt, of a compound of the formula II in which J is HO—. Likewise, in all other reactions in the preparation of the compounds of the formula I, including the preparation of starting compounds, compounds can also be employed and/or products obtained in the form a salt.
  • In case a compound of the formula II is employed in which J is HO—, the carboxylic acid group HO—C(O)— is generally activated in situ by means of a customary amide coupling reagent or converted into a reactive carboxylic acid derivative which can be prepared in situ or isolated. For example, the compound of the formula II in which J is HO— can be converted into an acid halide, such as the compound of the formula II in which J is chlorine or bromine, by treatment with thionyl chloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride, or treated with an alkyl chloroformate like ethyl chloroformate or isobutyl chloroformate to give a mixed anhydride. In a favorable method for the conversion into the acid chloride, the acid is treated with oxalyl chloride in the presence of a catalytic amount of an amide such as N,N-dimethylformamide in an inert solvent such as a hydrocarbon or chlorinated hydrocarbon or an ether, at temperatures from about 0° C. to about 60° C., for example at room temperature. Customary amide coupling reagents which can be employed, are propanephosphonic anhydride, N,N′-carbonyldiazoles like N,N′-carbonyldiimidazole (CDI), carbodiimides like 1,3-diisopropylcarbodiimide (DIC), 1,3-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbodiimides together with additives like 1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), uronium-based coupling reagents like O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or O-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU), and phosphonium-based coupling reagents like (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP).
  • The reaction conditions for the preparation of the compounds of the formula I from compounds of the formulae II and III depend on the particulars of the specific case, for example the meaning of the group J or the employed coupling reagent, and are familiar to a skilled person in view of the general knowledge in the art. For example, in case a compound of the formula II in which J is alkyl-O—, like methoxy or ethoxy, is reacted with a compound of the formula III, generally the reaction is carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform or dichloroethane, an ether like tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME), or a mixture of solvents, at elevated temperatures, for example at temperatures from about 40° C. to about 140° C., in particular at temperatures from about 50° C. to about 120° C., for example at about the boiling temperature of the solvent. In case a compound of the formula II in which J is halogen, like chlorine or bromine, is reacted with a compound of the formula III, generally the reaction is likewise carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon or ether like the aforementioned ones, an ester like ethyl acetate or butyl acetate, a nitrile like acetonitrile, or water, or a mixture of solvents including a mixture of water and an organic solvent which is miscible or immiscible with water, at temperatures from about −10° C. to about 100° C., in particular at temperatures from about 0° C. to about 80° C., for example at about room temperature. Favorably, the reaction of a compound of the formula II in which J is halogen with a compound of the formula III is carried out in the presence of a base such as a tertiary amine, like triethylamine, N-ethyl-diisopropylamine (EDIA), N-methylmorpholine, N-ethylmorpholine or pyridine, or an inorganic base such as an alkaline metal hydroxide, carbonate or hydrogencarbonate, like sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate.
  • In case a compound of the formula II in which J is HO— is reacted with a compound of the formula III and the carboxylic acid group is activated by means of an amide coupling reagent such as, for example, a carbodiimide or TOTU, the reaction is generally carried out under anhydrous conditions in an inert aprotic solvent, for example an ether like THF, dioxane or DME, an amide like N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), at temperatures from about −10° C. to about 40° C., in particular at temperatures from about 0° C. to about 30° C., for example at room temperature, in the presence of a base such as a tertiary amine, like triethylamine, EDIA, N-methylmorpholine or N-ethylmorpholine. In case the compound of the formula III is employed in the form of an acid addition salt in the reaction with the compound of the formula II, usually a sufficient amount of a base is added in order to liberate the free compound of the formula III.
  • As indicated above, during the formation of the amide bond between the compounds of the formulae II and III functional groups in the compounds of the formulae II and III can be present in protected form or in the form of a precursor group. Depending on the particulars of the specific case, it may be necessary or advisable for avoiding an undesired course of the reaction or side reactions to temporarily block any functional groups by protective groups and remove them later, or to let functional groups be present in the form of a precursor group which is later converted into the desired final group. This applies correspondingly to all reactions in the course of the synthesis of the compounds of the formula I including the synthesis of intermediates, starting compounds and building blocks. Respective synthetic strategies are commonly used in the art. Details about protective groups and their introduction and removal are described in P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4. ed. (2007), John Wiley & Sons, for example. Examples of protective groups which may be mentioned, are benzyl protective groups which may occur in the form of benzyl ethers of hydroxy groups and benzyl esters of carboxylic acid groups from which the benzyl group can be removed by catalytic hydrogenation in the presence of a palladium catalyst, tert-butyl protective groups which may occur in the form of tert-butyl esters of carboxylic acid groups from which the tert-butyl group can be removed by treatment with trifluoroacetic acid, acyl protective groups which may be used to protect hydroxy groups and amino groups in the form of esters and amides and which can be cleaved by acidic or basic hydrolysis, and alkyloxycarbonyl protective groups which may occur in the form of tert-butoxycarbonyl derivatives of amino groups which can be cleaved by treatment with trifluoroacetic acid. Undesired reactions of carboxylic acid groups, for example the carboxylic acid group present in the compound of the formula III in case G is a carboxylic acid group in the desired compound of the formula I, can also be avoided by employing them in the reaction with the compounds of the formula II in the form of other esters, for example in the form of alkyl esters like the methyl or ethyl ester which can be cleaved by hydrolysis, for example by means of an alkaline metal hydroxide like sodium hydroxide or lithium hydroxide. As examples of a precursor group, the cyano group (NC—, N≡C—) may be mentioned which can be converted into a carboxylic acid group, a carboxylic acid ester group and a carboxamide group under hydrolytic conditions or into a aminomethyl group by reduction, and the nitro group which can be converted into an amino group by reduction, for example by catalytic hydrogenation or by reduction with sodium dithionite, for example. A further example of a precursor group is an oxo group, which may initially be present in the course of the synthesis of compounds of the formula I containing a hydroxy group, and which can be reduced, for example with a complex hydride such as sodium borohydride, or reacted with an organometallic compound, for example a Grignard compound. If any protective groups or precursor groups are present in the compounds of the formulae II and III and the direct product of the reaction is not yet the desired final compound, the removal of the protective group or conversion into the desired compound can in general also be carried out in situ.
  • The starting compounds for the synthesis of the compounds of the formula I can generally be prepared according to procedures described in the literature or analogously to such procedures, or are commercially available.
  • The β-amino acids and derivatives of the formula III are commercially available or can be synthesized by well-known standard methods, or analogously to such methods, from readily available starting compounds. For example, for the preparation of β-amino acids and their alkyl esters of the formula III in which R50 and R60 are hydrogen, can carbonyl compounds of the formula R30—C(O)—R40, in particular aldehydes of the formula R32—C(O)—H, be reacted with malonic acid mono-ethyl ester and ammonia in the presence of a base such as an alkaline metal hydroxide like potassium hydroxide in a solvent such as an alcohol like ethanol, as described in V. M. Rodionov et al., Izv. Akad. Nauk SSSR, Ser. Khim. (1952), 696-702 (Chem. Abstr. 47 (1953), abstr. no. 61888), or ammonia added to the double bond in the condensation product of the carbonyl compound with malonic acid or diethyl malonate and in the case of the condensation product with diethyl malonate the reaction product treated with an acid such as hydrochloric acid, as described in V. Scudi, J. Am. Chem. Soc. 57 (1935), 1279; or M. K. Tse et al., Chem. Eur. J. 12 (2006), 1855-1874, and in the obtained product an ester group hydrolyzed to the carboxylic acid, or a carboxylic acid group esterified, respectively, as desired and outlined above. Enantiomerically pure such compounds of the formula III, for example, can be obtained from the racemic compounds by crystallization of a salt with an optically active acid, such as tartaric acid, by stereoselective enzymatic or microbial degradation, for example as described in the mentioned article by M. K. Tse et al., or in J. Mano et al., Bioscience, Biotechnology and Biochemistry 70 (2006), 1941-1946. In another strategy for the synthesis of such compounds, in particular compounds in which R40, R50 and R60 are hydrogen and R30 is R32, the respective 3-substituted acrylic acid, which can be obtained from the corresponding aldehyde, is converted into the acid chloride, for example with oxalyl chloride, and the acid chloride converted with an alcohol into an ester, for example into the tert-butyl ester using tert-butanol, and the amino group is then introduced by reaction with the lithium salt of an optically active amine, for example the lithium salt of (R)-(+)—N-benzyl-N-(1-phenylethyl)amine, and in the obtained 3-substituted tert-butyl 3-(N-benzyl-N-(1-phenylethyl)amino)propionate the benzyl group and the phenylethyl group is cleaved off by means of catalytic hydrogenation (cf. S. G. Davies et al., Tetrahedron: Asymmetry 2 (1991), 183-186); S. G. Davies et al., J. Chem. Soc. Perkin Trans. 1 (1994), 1129-1139).
  • The introduction of the structural moieties of the compounds of the formula in the course of the synthesis can also occur in another order than outlined above. For example, in the case of compounds of the formula I in which R10 is another group than hydroxy, instead of preparing a compound of the formula II which contains the group R10 and reacting it with a compound of the formula III, also a compound of the formula IIc, which specifically comprises a hydroxy group in place of the group R10, can be reacted with a compound of the formula III, and the obtained compound of the formula Ia then modified on the hydroxy group by reaction with a compound of the formula VIII to give a compound of the formula I in which R10 is different from hydroxy, i.e. a compound of the formula Ib. At the end, like in the compounds of the formula I when prepared as outlined above, any protective groups in the compounds of the formula Ib may still be deprotected and/or precursor group converted into the final groups.
  • Figure US20140135328A1-20140515-C00011
  • The groups A, D, E, L, G, R30, R40, R50 and R60 in the compounds of the formulae Ia, Ib and IIc are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group which is later converted into the final group. The group J in the compounds of the formula IIc is defined as in the compounds of the formula II. The group R10a in the compounds of the formula Ib is defined as in the compounds of the formulae IIb and VIII. The explanations given above on the reaction of the compounds of the formulae II and III and the reaction of the compounds of the formulae IIa and VIII apply correspondingly to the reaction of the compounds of the formulae IIc and III and the reaction of the compounds Ia and VIII, respectively.
  • For obtaining further compounds of the formula I, various transformations of functional groups can be carried out under standard conditions in compounds of the formula I or intermediates or starting compounds of the synthesis of the compounds of the formula I. For example, a hydroxy group, including a hydroxy group representing R10 in a compound of the formula I, can be etherified, as outlined above, for example by alkylation with a halogen compound, for example a bromide or iodide, in the presence of a base such an alkali metal carbonate like potassium carbonate or cesium carbonate in an inert solvent such as an amide like DMF or NMP or a ketone like acetone or butan-2-one, or with the respective alcohol under the conditions of the Mitsunobu reaction referred to above. A hydroxy group can be esterified to give a carboxylic acid ester or a sulfonic acid ester, or converted into a halide by treatment with a halogenating agent. Halogen atoms can also be introduced by means of suitable halogenating agents which replace a hydrogen atom in the starting compound, for example by means of elemental bromine, sulfuryl chloride or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), which introduce a bromine, chlorine and fluorine substituent, respectively, for example in the 4-position of a compound of the formula IIb. A halogen atom can generally be replaced with a variety of groups in substitution reactions which may also be transition-metal catalyzed reactions. A nitro group can be reduced to an amino group, for example by catalytic hydrogenation. An amino group can be modified under standard conditions for alkylation, for example by reaction with a halogen compound or by reductive amination of a carbonyl compound, or for acylation or sulfonylation, for example by reaction with an activated carboxylic acid or a carboxylic acid derivate like an acid chloride or anhydride or a sulfonic acid chloride. A carboxylic ester group can be hydrolyzed under acidic or basic conditions to give a carboxylic acid. An acid group can be activated or converted into a reactive derivative as outlined above and reacted with an alcohol or an amine or ammonia to give an ester or amide. A primary amide can be dehydrated to give a nitrile. A sulfur atom in an alkyl-S— group or in a heterocyclic ring can be oxidized with a peroxide like hydrogen peroxide or a peracid to give a sulfoxide moiety S(O) or a sulfone moiety S(O)2. A carboxylic acid group, carboxylic acid ester group and a ketone group can be reduced to an alcohol, for example with a complex hydride such al lithium aluminium hydride, lithium borohydride or sodium borohydride, or reacted with an organometallic compound or a Grignard compound to give an alcohol. Primary and secondary hydroxy groups can also be oxidized to the oxo groups. All reactions in the preparation of the compounds of the formula I are known per se and can be carried out in a manner familiar to a person skilled in the art according to, or analogously to, procedures which are described in the standard literature, for example in Houben-Weyl, Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley & Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2. ed. (1999), John Wiley & Sons, and the references quoted therein.
  • Another subject of the present invention are the novel starting compounds and intermediates occurring in the synthesis of the compounds of the formula I, including the compounds of the formulae Ia, Ib, Ic, II, IIc, III, IIIa, IV, V and VIII, wherein the groups A, D, E, L, G, J, T, R2, R10, R10a, R30, R40, R50 and R60 are defined as above, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their salts, and solvates of any of them, and their use as synthetic intermediates or starting compounds. All general explanations, specifications of embodiments and definitions of numbers and groups given above with respect to the compounds of the formula I apply correspondingly to the said intermediates and starting compounds. A subject of the invention are in particular the novel specific starting compounds and intermediates described herein. Independently thereof whether they are described as a free compound and/or as a specific salt, they are a subject of the invention both in the form of the free compounds and in the form of their salts, and if a specific salt is described, additionally in the form of this specific salt.
  • The compounds of the formula I inhibit the protease cathepsin A as can be demonstrated in the pharmacological test described below and in other tests which are known to a person skilled in the art. The compounds of the formula I and their physiologically acceptable salts and solvates therefore are valuable pharmaceutical active compounds. The compounds of the formula I and their physiologically acceptable salts and solvates can be used for the treatment of cardiovascular diseases such as heart failure including systolic heart failure, diastolic heart failure, diabetic heart failure and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction including left ventricular dysfunction after myocardial infarction, cardiac hypertrophy, myocardial remodeling including myocardial remodeling after infarction or after cardiac surgery, valvular heart diseases, vascular hypertrophy, vascular remodeling including vascular stiffness, hypertension including pulmonary hypertension, portal hypertension and systolic hypertension, atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis, thrombosis and vascular permeability disorders, ischemia and/or reperfusion damage including ischemia and/or reperfusion damage of the heart and ischemia and/or reperfusion damage of the retina, inflammation and inflammatory diseases such as rheumatoid arthritis and osteoarthritis, renal diseases such as renal papillary necrosis and renal failure including renal failure after ischemia/reperfusion, pulmonary diseases such as cystic fibrosis, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory dystress syndrome (ARDS), respiratory tract infections and lung carcinoma, immunological diseases, diabetic complications including diabetic nephropathy and diabetic cardiomyopathy, fibrotic diseases such as pulmonary fibrosis including idiopathic lung fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis including renal tubulointerstitial fibrosis, fibrosing skin conditions including keloid formation, collagenosis and scleroderma, and liver fibrosis, liver diseases such as liver cirrhosis, pain such as neuropathic pain, diabetic pain and inflammatory pain, macular degeneration, neurodegenerative diseases or psychiatric disorders, or for cardioprotection including cardioprotection after myocardial infarction and after cardiac surgery, or for renoprotection, for example. The treatment of diseases is to be understood as meaning both the therapy of existing pathological changes or malfunctions of the organism or of existing symptoms with the aim of relief, alleviation or cure, and the prophylaxis or prevention of pathological changes or malfunctions of the organism or of symptoms in humans or animals which are susceptible thereto and are in need of such a prophylaxis or prevention, with the aim of a prevention or suppression of their occurrence or of an attenuation in the case of their occurrence. For example, in patients who on account of their disease history are susceptible to myocardial infarction, by means of the prophylactic or preventive medicinal treatment the occurrence or re-occurrence of a myocardial infarction can be prevented or its extent and sequelae decreased, or in patients who are susceptible to attacks of asthma, by means of the prophylactic or preventive medicinal treatment such attacks can be prevented or their severity decreased. The treatment of diseases can occur both in acute cases and in chronic cases. The efficacy of the compounds of the formula I can be demonstrated in the pharmacological test described below and in other tests which are known to a person skilled in the art. The compounds of the formula I with G selected from R72—N(R73)—C(O)— and their physiologically acceptable salts and solvates can also be used as prodrugs.
  • The compounds of the formula I and their physiologically acceptable salts and solvates can therefore be used in animals, in particular in mammals and specifically in humans, as a pharmaceutical or medicament on their own, in mixtures with one another or in the form of pharmaceutical compositions. A subject of the present invention also are the compounds of the formula I and their physiologically acceptable salts and solvates for use as a pharmaceutical, as well as pharmaceutical compositions and medicaments which comprise an efficacious dose of at least one compound of the formula I and/or a physiologically acceptable salt thereof and/or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically innocuous, or nonhazardous, vehicles and/or excipients, and optionally one or more other pharmaceutical active compounds. A subject of the present invention furthermore are the compounds of the formula I and their physiologically acceptable salts and solvates for use in the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of heart failure, myocardial infarction, cardiac hypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemia and/or reperfusion damage, or for cardioprotection, the use of the compounds of the formula I and their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of heart failure, myocardial infarction, cardiac hypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemia and/or reperfusion damage, or for cardioprotection, wherein the treatment of diseases comprises their therapy and prophylaxis as mentioned above, as well as their use for the manufacture of a medicament for the inhibition of cathepsin A. A subject of the invention also are methods for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of heart failure, myocardial infarction, cardiac hypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemia and/or reperfusion damage, or for cardioprotection, which comprise administering an efficacious amount of at least one compound of the formula I and/or a physiologically acceptable salt thereof and/or solvate thereof to a human or an animal which is in need thereof. The compounds of the formula I and pharmaceutical compositions and medicaments comprising them can be administered enterally, for example by oral, sublingual or rectal administration, parenterally, for example by intravenous, intramuscular, subcutaneous or intraperitoneal injection or infusion, or by another type of administration such as topical, percutaneous, transdermal, intra-articular or intraocular administration.
  • The compounds of the formula I and their physiologically acceptable salts and solvates can also be used in combination with other pharmaceutical active compounds, wherein in such a combination use the compounds of the formula I and/or their physiologically acceptable salts and/or solvates and one or more other pharmaceutical active compounds can be present in one and the same pharmaceutical composition or in two or more pharmaceutical compositions for separate, simultaneous or sequential administration. Examples of such other pharmaceutical active compounds are diuretics, aquaretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, renin inhibitors, beta blockers, digoxin, aldosterone antagonists, NO donors, nitrates, hydralazines, ionotropes, vasopressin receptor antagonists, soluble guanylate cyclase activators, statins, peroxisome proliferator-activated receptor-alpha (PPAR-α) activators, peroxisome proliferator-activated receptor-gamma (PPAR-γ) activators, rosiglitazone, pioglitazone, metformin, sulfonylureas, glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase IV (DPPIV) inhibitors, insulins, anti-arrhythmics, endothelin receptor antagonists, calcium antagonists, phosphodiesterase inhibitors, phosphodiesterase type 5 (PDE5) inhibitors, factor II/factor IIa inhibitors, factor IX/factor IXa inhibitors, factor X/factor Xa inhibitors, factor XIII/factor XIIIa inhibitors, heparins, glycoprotein IIb/IIIa antagonists, P2Y12 receptor antagonists, clopidogrel, coumarins, cyclooxygenase inhibitors, acetylsalicylic acid, RAF kinase inhibitors and p38 mitogen-activated protein kinase inhibitors. A subject of the present invention also is the said combination use of any one or more of the compounds of the formula I disclosed herein and their physiologically acceptable salts and solvates, with any one or more, for example one or two, of the mentioned other pharmaceutical active compounds.
  • The pharmaceutical compositions and medicaments according to the invention normally contain from about 0.5 to about 90 percent by weight of compounds of the formula I and/or physiologically acceptable salts and/or solvates thereof, and an amount of active ingredient of the formula I and/or its physiologically acceptable salt and/or solvate which in general is from about 0.2 mg to about 1.5 g, particularly from about 0.2 mg to about 1 g, more particularly from about 0.5 mg to about 0.5 g, for example from about 1 mg to about 0.3 g, per unit dose. Depending on the kind of the pharmaceutical composition and other particulars of the specific case, the amount may deviate from the indicated ones. The production of the pharmaceutical compositions and medicaments can be carried out in a manner known per se. For this, the compounds of the formula I and/or their physiologically acceptable salts and/or solvates are mixed together with one or more solid or liquid vehicles and/or excipients, if desired also in combination with one or more other pharmaceutical active compounds such as those mentioned above, and brought into a suitable form for dosage and administration, which can then be used in human medicine or veterinary medicine.
  • As vehicles, which may also be looked upon as diluents or bulking agents, and excipients suitable organic and inorganic substances can be used which do not react in an undesired manner with the compounds of the formula I. As examples of types of excipients, or additives, which can be contained in the pharmaceutical compositions and medicaments, lubricants, preservatives, thickeners, stabilizers, disintegrants, wetting agents, agents for achieving a depot effect, emulsifiers, salts, for example for influencing the osmotic pressure, buffer substances, colorants, flavorings and aromatic substances may be mentioned. Examples of vehicles and excipients are water, vegetable oils, waxes, alcohols such as ethanol, isopropanol, 1,2-propanediol, benzyl alcohols, glycerol, polyols, polyethylene glycols or polypropylene glycols, glycerol triacetate, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose or starch like corn starch, sodium chloride, stearic acid and its salts such as magnesium stearate, talc, lanolin, petroleum jelly, or mixtures thereof, for example saline or mixtures of water with one or more organic solvents such as mixtures of water with alcohols. For oral and rectal use, pharmaceutical forms such as, for example, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, including oily, alcoholic or aqueous solutions, syrups, juices or drops, furthermore suspensions or emulsions, can be used. For parenteral use, for example by injection or infusion, pharmaceutical forms such as solutions, for example aqueous solutions, can be used. For topical use, pharmaceutical forms such as ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions or powders can be used. Further suitable pharmaceutical forms are, for example, implants and patches and forms adapted to inhalation. The compounds of the formula I and their physiologically acceptable salts can also be lyophilized and the obtained lyophilizates used, for example, for the production of injectable compositions. In particular for topical application, also liposomal compositions are suitable. The pharmaceutical compositions and medicaments can also contain one or more other active ingredients and/or, for example, one or more vitamins.
  • As usual, the dosage of the compounds of the formula I depends on the circumstances of the specific case and is adjusted by the physician according to the customary rules and procedures. It depends, for example, on the compound of the formula I administered and its potency and duration of action, on the nature and severity of the individual syndrome, on the sex, age, weight and the individual responsiveness of the human or animal to be treated, on whether the treatment is acute or chronic or prophylactic, or on whether further pharmaceutical active compounds are administered in addition to a compound of the formula I. Normally, in the case of administration to an adult weighing about 75 kg, a dose from about 0.1 mg to about 100 mg per kg per day, in particular from about 1 mg to about 20 mg per kg per day, for example from about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight), is administered. The daily dose can be administered in the form of a single dose or divided into a number of individual doses, for example two, three or four individual doses. The administration can also be carried out continuously, for example by continuous injection or infusion. Depending on the individual behavior in a specific case, it may be necessary to deviate upward or downward from the indicated dosages.
  • Besides as a pharmaceutical active compound in human medicine and veterinary medicine, the compounds of the formula I can also be employed as an aid in biochemical investigations or as a scientific tool or for diagnostic purposes, for example in in-vitro diagnoses of biological samples, if an inhibition of cathepsin A is intended. The compounds of the formula I and their salts can also be used as intermediates, for example for the preparation of further pharmaceutical active substances.
  • The following examples illustrate the invention.
    • Abbreviations
  • ACN acetonitrile
    DCM dichloromethane
    • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
    EA ethyl acetate
    • EDIA N-ethyl-diisopropylamine
  • FA formic acid
    MOH methanol
    • NEM N-ethyl-morpholine
  • TFA trifluoroacetic acid
    THF tetrahydrofuran
    TOTU O-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • When example compounds containing a basic group were purified by preparative high pressure liquid chromatography (HPLC) on reversed phase (RP) column material and, as customary, the eluent was a gradient mixture of water and acetonitrile containing trifluoroacetic acid, they were in part obtained in the form of their acid addition salts with trifluoroacetic acid, depending on the details of the work-up such as evaporation or lyophilization conditions. In the names of the example compounds and the structural formulae such contained trifluoroacetic acid is not specified. Likewise are other acid components of example compounds obtained in the form of an acid addition salt in general not specified in the name and the formula.
  • The prepared compounds were in general characterized by spectroscopic data and chromatographic data, in particular mass spectra (MS) and HPLC retention times (Rt; in min) which were obtained by combined analytical HPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance (NMR) spectra. Unless specified otherwise, 1H-NMR spectra were recorded at 500 MHz in D6-DMSO as solvent at 298 K. In the NMR characterization, the chemical shift δ (in ppm), the number of hydrogen atoms (H), and the multiplicity (s: singlet, d: doublet, dd: doublet of doublets, t: triplet, q: quartet, m: multiplet) of the peaks as determined from the graphically depicted spectra are given. In the MS characterization, in general the mass number (m/z) of the peak of the molecular ion [M], for example [M+], or of a related ion such as the ion [M+1], for example [(M+1)+], i.e. the protonated molecular ion [(M+H)+], or the ion [M−1], for example [(M−1)−], i.e. the deprotonated molecular ion [(M−H)−], which was formed depending on the ionization method used, is given. Generally, the ionization method was electrospray ionization (ES). The particulars of the LC/MS methods used are as follows.
    • Method LC1
  • Column: YMC-Pack Jsphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; room temperature; eluent A: water+0.05% TFA; eluent B: ACN+0.05% TFA; gradient: from 95% A+5% B to 5% A+95% B within 2.5 min; MS ionization method: ES+
    • Method LC2
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min; room temperature; eluent A: water+0.1% FA; eluent B: ACN+0.08% FA; gradient: from 97% A+3% B to 40% A+60% B within 3.5 min, then to 2% A+98% B within 0.5 min, then 2% A+98% B for 1.0 min, then to 97% A+3% B within 0.2 min, then 97% A+3% B for 1.3 min; MS ionization method: ES−
    • Method LC3
  • Column: YMC-Pack Jsphere H80, 33×2.1 mm, 4 μm; flow: 1.0 ml/min; room temperature; eluent A: water+0.05% TFA; eluent B: ACN+0.05% TFA; gradient: 98% A+2% B for 1.0 min, then to 5% A+95% B within 4.0 min, then 5% A+95% B for 1.25 min; MS ionization method: ES+
    • Method LC4
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min; 40° C.; eluent A: water+0.1% FA; eluent B: ACN+0.1% FA; gradient: from 97% A+3% B to 40% A+60% B within 3.5 min, then to 2% A+98% B within 0.5 min, then 2% A+98% B for 1.0 min, then to 97% A+3% B within 0.2 min, then 97% A+3% B for 1.3 min; MS ionization method: ES−
    • Method LC5
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 40° C.; eluent A: water+0.05% TEA; eluent B: ACN+0.05% TFA; gradient: from 95% A+5% B to 5% A+95% B within 3.3 min, then 5% A+95% B for 0.55 min, then to 95% A+5% B within 0.15 min; MS ionization method: ES+
    • Method LC6
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 50° C.; eluent A: water+0.05% TEA; eluent B: ACN+0.05% TFA; gradient: 95% A+5% B for 0.2 min, then to 5% A+95% B within 2.2 min, then 5% A+95% B for 1.1 min, then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.9 min; MS ionization method: ES+
    • Method LC7
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 40° C.; eluent A: water+0.05% TFA; eluent B: ACN+0.05% TEA; gradient: 95% A+5% B for 0.2 min, then to 5% A+95% B within 2.2 min, then 5% A+95% B for 0.8 min, then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.7 min; MS ionization method: ES+
    • Method LC8
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 40° C.; eluent A: water+0.05% TEA; eluent B: ACN+0.05% TEA; gradient: 95% A+5% B for 0.3 min, then to 5% A+95% B within 3.2 min, then 5% A+95% B for 0.5 min; MS ionization method: ES+
    • Method LC9
  • Column: Merck Chromolith FastGrad RP-18e, 50×2 mm; flow: 2.0 ml/min; room temperature; eluent A: water+0.05% TFA; eluent B: ACN+0.05% TFA; gradient: 98% A+2% B for 0.2 min, then to 2% A+98% B within 2.2 min, then 2% A+98% B for 0.8 min, then to 98% A+2% B within 0.1 min, then 98% A+2% B for 0.7 min; MS ionization method: ES+
    • Method LC10
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min; 45° C.; eluent A: water+0.1% FA; eluent B: ACN+0.1% FA; gradient: from 97% A+3% B to 40% A+60% B within 3.5 min, then to 2% A+98% B within 0.5 min, then 2% A+98% B for 1.0 min, then to 97% A+3% B within 0.2 min, then 97% A+3% B for 1.3 min; MS ionization method: ES+
    • Method LC11
  • Column: Waters UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow: 0.9 ml/min; 55° C.; eluent A: water+0.1% FA; eluent B: ACN+0.08% FA; gradient: from 95% A+5% B to 5% A+95% B within 1.1 min, then 5% A+95% B for 0.6 min, then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.2 min; MS ionization method: ES+
    • Method LC11—2
  • Column: Waters UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow: 0.9 ml/min; 55° C.; eluent A: water+0.05% FA; eluent B: ACN+0.035% FA; gradient: from 95% A+5% B to 5% A+95% B within 1.1 min, then 5% A+95% B for 0.6 min, then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.2 min; MS ionization method: ES+
    • Method LC11—3
  • Column: Waters UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow: 0.9 ml/min; 55° C.; eluent A: water+0.05% FA; eluent B: ACN+0.035% FA; gradient: from 95% A+5% B to 5% A+95% B within 1.1 min, then 5% A+95% B for 0.6 min, then to 95% A+5% B within 0.2 min, then 95% A+5% B for 0.1 min; MS ionization method: ES+
    • Method LC11_X
  • Column: Waters UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow: 0.9 ml/min; 55° C.; eluent A: water+0.05% TFA; eluent B: ACN+0.035% TFA; gradient: from 98% A+2% B to 5% A+95% B within 2.0 min, then 5% A+95% B for 0.6 min, then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.3 min; MS ionization method: ES+
    • Method LC_X
  • Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 40° C.; eluent A: water+0.05% TFA; eluent B: ACN+0.05% TFA; gradient: from 95% A+5% B to 95% A+5% B within 0.2 min, then to 5% A+95% B within 2.2 min, then 5% A+95% B for 0.8 min, then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.7 min; MS ionization method: ES+
    • Method LC12
  • Column: YMC-Pack Jsphere H80, 33×2.1 mm, 4 μm; flow: 1.0 ml/min; room temperature; eluent A: water+0.05% TFA; eluent B: MOH+0.05% TEA; gradient: 98% A+2% B for 1.0 min, then to 5% A+95% B within 4.0 min, then 5% A+95% B for 1.25 min; MS ionization method: ES+
    • Method LC13.
  • Column: Waters XBridge C18, 50×4.6, 2.5 μm; flow: 1.3 ml/min; room temperature; eluent A: water+0.1% FA; eluent B: ACN+0.08% FA; gradient: from 97% A+3% B to 2% A+98% B within 18.0 min, then 2% A+98% B for 1.0 min, then to 97% A+3% B within 0.5 min, then 97% A+3% B for 0.5 min; MS ionization method: ES+
    • Method LC14
  • Column: Waters XBridge C18 4.6*50 mm; 2,5 um, flow: 1.3 ml/min; eluent A H2O+0.1% FA; eluent B: ACN+0.08% FA; gradient: from 97% A+3% B to 2% A+98% B within 18 min, then 2% A+98% B for 1 min, then to 97% A+3% B within 0.5 min then to 97:3 for 0.5 min.
  • Analogously as described in the synthesis examples, the example compounds of the formula I listed in Table 1 were prepared.
  • TABLE 1
    Example compounds of the formula I
    LC/MS Activity
    Ex. No. Compound name m/z (1) Rt (min) Method [μM]
    1 (S)-3-[(5-Methoxy-6-phenyl- 391.19 1.27 LC11 0.1231
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    2 (S)-3-(2,4-Dichloro-phenyl)- 445.1 1.33 LC11 0.547
    3-[(5-methoxy-6-phenyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    3 (S)-3-[(6-Chloro-5-methoxy- 349.09 1.06 LC11 0.274
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    4 (S)-3-{[3-(4,6-Dimethoxy- 439.17 1.19 LC11 0.353
    pyrimidin-2-yloxy)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    5 (S)-3-[(Pyridine-2-carbonyl)- 285.14 1.13 LC11 3.98
    amino]-3-o-tolyl-propionic
    acid
    6 (S)-3-[(Pyridine-4-carbonyl)- 285.16 0.97 LC11
    amino]-3-o-tolyl-propionic
    acid
    7 (S)-3-[(5-Bromo-pyridine-3- 363.04 1.14 LC11 >10.0
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    8 (S)-3-[(Pyridine-3-carbonyl)- 285.16 0.99 LC11 10.4
    amino]-3-o-tolyl-propionic
    acid
    9 (S)-3-[(3-Methoxy-pyridine-2- 315.18 1.04 LC11 7.25
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    10 (S)-3-[(6-Methyl-pyridine-2- 299.17 1.18 LC11 1.24
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    11 (S)-3-[(4,6-Dimethyl- 313.2 0.92 LC11 >10.0
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    12 (S)-3-[(6-Methylamino- 315.17 1.08 LC11 7.32
    pyrazine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    13 (S)-3-[(2,6-Bis- 372.24 3.25 LC2 10.1
    dimethylamino-pyrimidine-4-
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    14 (S)-3-[(4-Methyl-pyridine-2- 299.17 1.18 LC11 4.35
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    15 (S)-3-[(5-Phenyl-pyridine-3- 361.32 3.85 LC2 2.16
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    16 (S)-3-[(2,6-Dimethoxy- 346.15 1.2 LC11 1.05
    pyrimidine-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    17 (S)-3-[([1,6]Naphthyridine-2- 336.16 1.09 LC11 3.09
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    18 (S)-3-[(4-Ethyl-pyridine-2- 313.2 1.22 LC11 3.06
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    19 (S)-3-[(2-Acetylamino- 342.17 1.03 LC11 >10.0
    pyridine-4-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    20 (S)-3-[(3,4,5,6-Tetrahydro- 368.22 1.04 LC11
    2H-[1,2′]bipyridinyl-4′-
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    21 (S)-3-[(2-Methoxy-pyridine-4- 315.17 1.12 LC11
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    22 (S)-3-{[2-(2,2-Dimethyl- 384.2 1.17 LC11
    propionylamino)-pyridine-4-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    23 (S)-3-[(6-Bromo-5-methoxy- 393.05 1.21 LC11 0.564
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    24 (S)-3-[(6-Methoxy-pyridine-3- 315.17 1.11 LC11
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    25 (S)-3-[(6-Morpholin-4-yl- 370.19 1.17 LC11
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    26 (S)-3-[(2-Pyrrolidin-1-yl- 354.22 0.97 LC11
    pyridine-4-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    27 (S)-3-[(1-Ethyl-3,6-dimethyl- 381.23 1.15 LC11
    1H-pyrazolo[3,4-b]pyridine-
    4-carbonyl)-amino]-3-o-tolyl-
    propionic acid
    28 (S)-3-[(6-Cyclopropyl-1,3- 393.21 1.2 LC11
    dimethyl-1H-pyrazolo[3,4-
    b]pyridine-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    29 (S)-3-[(2-Morpholin-4-yl- 370.21 1.03 LC11
    pyridine-4-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    30 (S)-3-[(4,6-Dimethoxy- 344.27 1.15 LC11 4.21
    pyrimidine-2-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    31 (S)-3-[(6-Methoxy-pyridine-2- 315.17 1.19 LC11 4.77
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    32 (S)-3-{[6-(Tetrahydro-pyran- 385.18 1.14 LC11
    4-yloxy)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    33 (S)-3-[(3-Fluoro-pyridine-2- 301.26 1.1 LC11 3.42
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    34 (S)-3-[(3H-Imidazo[4,5- 325.16 1 LC11 5.07
    b]pyridine-5-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid; compound with
    trifluoro-acetic acid
    35 (S)-3-{[4-(Pyrimidin-2- 395.13 1.19 LC11 0.844
    ylsulfanyl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    36 (S)-3-[(2-Methyl-pyridine-4- 299.18 0.94 LC11
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    37 (S)-3-[(6-Phenyl-pyridine-2- 361.2 1.14 LC11_2 0.1302
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    38 (S)-3-[(3-Phenyl-pyridine-2- 361.17 1.19 LC11
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    39 (S)-3-[(4-Phenyl-pyridine-2- 361.19 1.28 LC11 1.08
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    40 (S)-3-[(5-Phenyl-pyridine-2- 361.18 1.28 LC11 0.45
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    41 (S)-3-[(5-Pyrrolidin-1-yl- 354.2 1.01 LC11
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid;
    compound with trifluoro-
    acetic acid
    42 (S)-3-[(5-Methyl-pyrazine-2- 298.26 1.1 LC11
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    43 (S)-3-{[6-(3-Methoxy- 391.19 1.14 LC11_2 2.27
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    44 (S)-3-{[6-(2-Methoxy- 391.23 1.14 LC11_2 1.192
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    45 (S)-3-{[6-(4-Methoxy- 391.18 1.26 LC11 3.09
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    46 (S)-3-[(6-Phenoxy-pyridine- 377.16 1.23 LC11 9.94
    3-carbonyl)-amino]-3-o-tolyl-
    propionic acid
    47 (S)-3-[(4-Hydroxy-pyridine-2- 301.14 0.97 LC11
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    48 (S)-3-[(6-Fluoro-pyridine-2- 301.28 1.15 LC11 1.67
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    49 (S)-3-[(6-Pyrrolidin-1-yl- 354.21 0.95 LC11
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    50 (S)-3-[(4-Morpholin-4-yl- 370.2 0.93 LC11 7.73
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    51 (S)-3-[(4,6-Dimethyl- 313.19 1.2 LC11 1.81
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    52 (S)-3-[(2-Amino-6-isobutyl- 357.03 1.18 LC11 3.68
    pyrimidine-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid; compound with
    trifluoro-acetic acid
    53 (S)-3-[(3,6-Difluoro-pyridine- 319.24 1.12 LC11 2.83
    2-carbonyl)-amino]-3-o-tolyl-
    propionic acid
    54 (S)-3-[(3,4,5,6-Tetrahydro- 368.22 1.3 LC11 8.93
    2H-[1,2′]bipyridinyl-6′-
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    55 (S)-3-[(2,6-Dimethyl- 314.19 1.11 LC11 5.26
    pyrimidine-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    56 (S)-3-[(6-Imidazol-1-yl- 351.16 0.95 LC11 11.1
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    57 (S)-3-{[5-(4-Methoxy- 391.23 1.17 LC11 11.46
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    58 (S)-3-[(6-Methoxy- 392.24 0.91 LC11_2 >30.0
    [2,4′]bipyridinyl-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid; compound with
    trifluoro-acetic acid
    59 (S)-3-[(6-Methoxy- 392.33 0.96 LC11_2 >30.0
    [2,3′]bipyridinyl-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid; compound with
    trifluoro-acetic acid
    60 (S)-3-o-Tolyl-3-{[5-(3- 429.41 4.36 LC2
    trifluoromethyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    propionic acid
    61 (S)-3-{[5-(2,4-Dichloro- 429.17 1.14 LC11_2 5.14
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    62 (S)-3-{[5-(4-Fluoro-phenyl)- 377.23 1.06 LC11_2
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    63 (S)-3-o-Tolyl-3-[(5-p-tolyl- 375.39 4.09 LC2
    pyridine-3-carbonyl)-amino]-
    propionic acid
    64 (S)-3-o-Tolyl-3-{[5-(4- 429.41 4.4 LC2
    trifluoromethyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    propionic acid
    65 (S)-3-{[5-(3-Methoxy- 391.41 3.91 LC2
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    66 (S)-3-o-Tolyl-3-{[5-(2- 429.34 4.21 LC2 4.29
    trifluoromethyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    propionic acid
    67 (S)-3-{[5-(2-Methoxy- 391.41 3.83 LC2 4.97
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    68 (S)-3-o-Tolyl-3-[(5-m-tolyl- 375.39 4.1 LC2
    pyridine-3-carbonyl)-amino]-
    propionic acid
    69 (S)-3-{[5-(2-Fluoro-phenyl)- 379.38 3.92 LC2 1.4
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    70 (S)-3-{[5-(3-Cyano-phenyl)- 386.38 3.78 LC2
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    71 (S)-3-{[5-(4-Cyano-phenyl)- 386.26 1.03 LC11_2
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    72 (S)-3-{[5-(3,4-Dimethoxy- 421.44 3.59 LC2
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    73 (S)-3-{[5-(2,4-Difluoro- 395.21 1.07 LC11_2 3.25
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    74 (S)-3-{[5-(3,4-Difluoro- 395.19 1.08 LC11_2
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    75 (S)-3-{[5-(2,6-Difluoro- 395.17 1.07 LC11_2
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    76 (S)-3-[(5-Benzo[1,3]dioxol-5- 405.34 3.78 LC2 8.04
    yl-pyridine-3-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    77 (S)-3-{[5-(3,4-Dimethyl- 389.39 4.29 LC2
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    78 (S)-3-o-Tolyl-3-{[5-(3,4,5- 451.31 1.03 LC11_2
    trimethoxy-phenyl)-pyridine-
    3-carbonyl]-amino}-propionic
    acid
    79 (S)-3-{[5-(2,3-Difluoro- 395.17 1.07 LC11_2 5.01
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    80 (S)-3-{[5-(2-Cyano-phenyl)- 386.23 1.02 LC11_2
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    81 (S)-3-{[5-(3,5-Dimethyl- 380.26 0.98 LC11_2
    isoxazol-4-yl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    82 (S)-3-{[5-(4-Fluoro-2-methyl- 393.37 4.13 LC2 3.08
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    83 (S)-3-[(5-Pyrimidin-5-yl- 363.22 0.88 LC11_2
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid;
    compound with trifluoro-
    acetic acid
    84 (S)-3-{[5-(2- 432.42 3.34 LC2
    Dimethylcarbamoyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    85 (S)-3-{[5-(4-Fluoro-2- 409.4 3.96 LC2 7.83
    methoxy-phenyl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    86 (S)-3-{[5-(2-Methoxy-4- 459.37 4.42 LC2
    trifluoromethyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    87 (S)-3-{[5-(1-Benzyl-1H- 441.45 3.78 LC2
    pyrazol-4-yl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    88 (S)-3-{[5-(2-Fluoro-5- 407.26 1.07 LC11_2 8.51
    methoxy-phenyl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    89 (S)-3-{[5-(2-Dimethylamino- 406.32 0.99 LC11_2
    pyrimidin-5-yl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid; compound
    with trifluoro-acetic acid
    90 (S)-3-[(2′-Morpholin-4-yl- 447.34 0.88 LC11_2
    [3,4′]bipyridinyl-5-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    91 (S)-3-[(5′-Fluoro- 380.22 0.97 LC11_2
    [3,3′]bipyridinyl-5-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    92 (S)-3-{[2-(4-Methoxy- 391.2 1.16 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    93 (S)-3-o-Tolyl-3-{[2-(4- 429.19 1.27 LC11
    trifluoromethyl-phenyl)-
    pyridine-4-carbonyl]-amino}-
    propionic acid
    94 (S)-3-{[2-(3-Methoxy- 391.23 1.18 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    95 (S)-3-{[2-(2-Methoxy- 391.22 1.13 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    96 (S)-3-o-Tolyl-3-[(2-m-tolyl- 375.23 1.22 LC11
    pyridine-4-carbonyl)-amino]-
    propionic acid
    97 (S)-3-{[2-(2-Fluoro-phenyl)- 379.2 1.17 LC11 2.71
    pyridine-4-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    98 (S)-3-{[2-(3,4-Dimethoxy- 421.23 1.13 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    99 (S)-3-{[2-(3,5-Difluoro- 397.18 1.24 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    100 (S)-3-{[2-(3,4-Difluoro- 397.2 1.23 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    101 (S)-3-[(2-Benzo[1,3]dioxol-5- 405.21 1.16 LC11
    yl-pyridine-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    102 (S)-3-o-Tolyl-3-{[2-(3,4,5- 451.26 1.16 LC11
    trimethoxy-phenyl)-pyridine-
    4-carbonyl]-amino}-propionic
    acid
    103 (S)-3-[([2,3′]Bipyridinyl-4- 362.19 0.98 LC11
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    104 (S)-3-{[2-(2,5-Dichloro- 429.16 1.24 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    105 (S)-3-{[2-(3,5-Dimethyl- 380.2 1.11 LC11
    isoxazol-4-yl)-pyridine-4-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    106 (S)-3-[(2′-Methyl- 376.21 0.94 LC11
    [2,4′]bipyridinyl-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    107 (S)-3-{[2-(4-Fluoro-2- 409.21 1.16 LC11
    methoxy-phenyl)-pyridine-4-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    108 (S)-3-{[2-(1-Benzyl-1H- 441.27 1.16 LC11
    pyrazol-4-yl)-pyridine-4-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid; compound
    with trifluoro-acetic acid
    109 (S)-3-{[2-(2-Fluoro-5- 409.21 1.18 LC11
    methoxy-phenyl)-pyridine-4-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    110 (S)-3-{[2-(3- 431.27 1.25 LC11
    Cyclopropylmethoxy-
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    111 (S)-3-{[5-(3-Chloro-4-fluoro- 413.23 1.11 LC11_2
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    112 (S)-3-{[5-(2-Chloro-phenyl)- 395.33 4.09 LC2 0.826
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    113 (S)-3-{[5-(4-tert-Butyl- 417.45 4.66 LC2
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    114 (S)-3-{[5-(2,3-Dichloro- 429.21 1.13 LC11_2 0.95
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    115 (S)-3-[([3,4′]Bipyridinyl-5- 362.21 0.8 LC11_2
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    116 (S)-3-{[5-(2,3-Dimethyl- 389.39 4.24 LC2 1.01
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    117 (S)-3-{[5-(2,4-Dimethyl- 389.39 4.29 LC2 5.27
    phenyl)-pyridine-3-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    118 (S)-3-[(2′-Methyl- 376.26 0.79 LC11_2
    [3,4′]bipyridinyl-5-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    119 (S)-3-{[5-(4-Chloro-2- 425.24 1.11 LC11_2
    methoxy-phenyl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    120 (S)-3-({5-[3-(5-Methyl- 443.3 1 LC11_2
    [1,3,4]oxadiazol-2-yl)-
    phenyl]-pyridine-3-carbonyl}-
    amino)-3-o-tolyl-propionic
    acid
    121 (S)-3-{[5-(3-Chloro-4- 466.27 0.99 LC11_2
    dimethylcarbamoyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    122 (S)-3-[(2-Biphenyl-3-yl- 437.27 1.29 LC11
    pyridine-4-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    123 (S)-3-{[2-(2,3-Dichloro- 429.12 1.23 LC11 3.7
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    124 (S)-3-{[2-(3,4-Dimethyl- 389.23 1.24 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    125 (S)-3-{[2-(2,3-Difluoro- 397.18 1.19 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    126 (S)-3-{[2-(2-Cyano-phenyl)- 386.18 1.14 LC11
    pyridine-4-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    127 (S)-3-{[2-(4-Fluoro-2-methyl- 393.2 1.2 LC11
    phenyl)-pyridine-4-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    128 (S)-3-{[2-(2-Methoxy-4- 459.22 1.25 LC11
    trifluoromethyl-phenyl)-
    pyridine-4-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    129 (S)-3-{[2-(4-Chloro-2- 425.17 1.21 LC11
    methoxy-phenyl)-pyridine-4-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    130 (S)-3-[(2′-Morpholin-4-yl- 447.27 1 LC11
    [2,4′]bipyridinyl-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    131 (S)-3-[(5′-Fluoro- 380.18 1.12 LC11
    [2,3′]bipyridinyl-4-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    132 (S)-3-({2-[3-(1-Hydroxy-1- 419.25 1.13 LC11
    methyl-ethyl)-phenyl]-
    pyridine-4-carbonyl}-amino)-
    3-o-tolyl-propionic acid
    133 (S)-3-o-Tolyl-3-{[6-(3- 429.18 1.19 LC11_2 5.76
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    134 (S)-3-{[6-(3-Chloro-4-fluoro- 413.14 1.19 LC11_2 3.62
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    135 (S)-3-{[6-(4-Fluoro-phenyl)- 379.17 1.15 LC11_2 1.18
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    136 (S)-3-{[6-(4-Chloro-phenyl)- 395.13 1.19 LC11_2 4.85
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    137 (S)-3-o-Tolyl-3-[(6-p-tolyl- 375.21 1.18 LC11_2 1.24
    pyridine-2-carbonyl)-amino]-
    propionic acid
    138 (S)-3-o-Tolyl-3-{[6-(4- 429.19 1.2 LC11_2 6.83
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    139 (S)-3-o-Tolyl-3-{[6-(2- 429.19 1.16 LC11_2 1.09
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    140 (S)-3-{[6-(3-Chloro-phenyl)- 395.18 1.18 LC11_2 1.57
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    141 (S)-3-o-Tolyl-3-[(6-m-tolyl- 375.21 1.18 LC11_2 0.1608
    pyridine-2-carbonyl)-amino]-
    propionic acid
    142 (S)-3-{[6-(2-Chloro-phenyl)- 395.14 1.16 LC11_2 0.05
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    143 (S)-3-{[6-(2-Fluoro-phenyl)- 379.16 1.15 LC11_2 0.0733
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    144 (S)-3-{[6-(4-tert-Butyl- 417.29 1.26 LC11_2
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    145 (S)-3-{[6-(3-Cyano-phenyl)- 386.21 1.11 LC11_2 7.46
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    146 (S)-3-{[6-(4-Cyano-phenyl)- 386.17 1.11 LC11_2 2.16
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    147 (S)-3-[(6-Biphenyl-3-yl- 437.26 1.24 LC11_2 3.16
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    148 (S)-3-{[6-(3,4-Dimethoxy- 421.22 1.1 LC11_2
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    149 (S)-3-{[6-(2,4-Difluoro- 397.16 1.16 LC11_2 4.4
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    150 (S)-3-{[6-(3,5-Difluoro- 397.15 1.16 LC11_2 1.02
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    151 (S)-3-{[6-(3,4-Difluoro- 397.18 1.16 LC11_2 1.18
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    152 (S)-3-[(6-Benzo[1,3]dioxol-5- 405.19 1.12 LC11_2 1.55
    yl-pyridine-2-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    153 (S)-3-{[6-(3,4-Dimethyl- 389.23 1.21 LC11_2 1.19
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    154 (S)-3-o-Tolyl-3-{[6-(3,4,5- 451.24 1.12 LC11_2
    trimethoxy-phenyl)-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    155 (S)-3-[([2,3′]Bipyridinyl-6- 362.17 0.93 LC11_2
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    156 (S)-3-{[6-(2,3-Difluoro- 397.18 1.16 LC11_2 0.272
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    157 (S)-3-{[6-(2-Cyano-phenyl)- 386.14 1.1 LC11_2 2.46
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    158 (S)-3-{[6-(2,5-Difluoro- 397.15 1.27 LC11 0.126
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    159 (S)-3-{[6-(3,5-Dimethyl- 380.15 1.18 LC11 14.4
    isoxazol-4-yl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    160 (S)-3-{[6-(4-Fluoro-2-methyl- 393.16 1.29 LC11 0.472
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    161 (S)-3-{[6-(2,3-Dimethyl- 389.19 1.31 LC11 0.0294
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    162 (S)-3-{[6-(2,4-Dimethyl- 389.17 1.32 LC11 1.43
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    163 (S)-3-[(2′-Methyl- 376.17 0.96 LC11
    [2,4′]bipyridinyl-6-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    164 (S)-3-[(6-Pyrimidin-5-yl- 363.15 1.09 LC11
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid;
    compound with trifluoro-
    acetic acid
    165 (S)-3-{[6-(5-Fluoro-2-methyl- 393.16 1.29 LC11 0.0944
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    166 (S)-3-{[6-(4-Fluoro-2- 409.16 1.27 LC11
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    167 (S)-3-{[6-(2-Methoxy-4- 459.18 1.32 LC11 0.963
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    168 (S)-3-{[6-(4-Chloro-2- 425.13 1.31 LC11 0.425
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    169 (S)-3-{[6-(1-Benzyl-1H- 441.19 1.23 LC11
    pyrazol-4-yl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid; compound
    with trifluoro-acetic acid
    170 (S)-3-{[6-(2-Fluoro-5- 409.16 1.28 LC11 0.815
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    171 (S)-3-{[6-(3- 431.22 1.33 LC11 6.98
    Cyclopropylmethoxy-
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    172 (S)-3-{[6-(3-Fluoro-2-methyl- 393.17 1.29 LC11 3.21
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    173 (S)-3-{[6-(2-Dimethylamino- 406.21 1.2 LC11
    pyrimidin-5-yl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid; compound
    with trifluoro-acetic acid
    174 (S)-3-{[6-(3-Chloro-4- 464.31 1.18 LC11 1.59
    dimethylcarbamoyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    175 (S)-3-{[6-(5-Chloro-2-fluoro- 427.13 1.34 LC11 2.36
    4-methyl-phenyl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    176 (S)-3-({6-[3-(1-Hydroxy-1- 419.2 1.2 LC11 3.32
    methyl-ethyl)-phenyl]-
    pyridine-2-carbonyl}-amino)-
    3-o-tolyl-propionic acid
    177 (S)-3-{[2-(2-Dimethylamino- 406.25 1.12 LC11
    pyrimidin-5-yl)-pyridine-4-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid; compound
    with trifluoro-acetic acid
    178 (S)-3-{[6-(2-Fluoro-phenyl)- 409.1 1.12 LC11_2 0.0683
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    179 (S)-3-{[2-(3-Chloro-phenyl)- 395.23 4.51 LC2
    pyridine-4-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    180 (S)-3-{[6-(2-Fluoro-5-methyl- 393.16 1.3 LC11 0.289
    phenyl)-pyridine-2-carbonyl]-
    amino}-3-o-tolyl-propionic
    acid
    181 (S)-3-{[5-Methoxy-6-(3- 459.28 1.19 LC11_2 5
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    182 (S)-3-[(5-Methoxy-6-phenyl- 389.28 1.14 LC11_2 0.232
    pyridine-2-carbonyl)-amino]-
    3-p-tolyl-propionic acid
    183 (S)-3-{[6-(2,4-Dichloro- 459.21 1.2 LC11_2 1.009
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    184 (S)-3-{[6-(3-Chloro-4-fluoro- 443.23 1.19 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    185 (S)-3-{[6-(4-Fluoro-phenyl)- 409.23 1.15 LC11_2 1.289
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    186 (S)-3-{[6-(4-Chloro-phenyl)- 425.25 1.18 LC11_2 3.56
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    187 (S)-3-{[5-Methoxy-6-(4- 419.32 1.13 LC11_2 4.85
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    188 (S)-3-[(5-Methoxy-6-p-tolyl- 403.31 1.17 LC11_2 4.45
    pyridine-2-carbonyl)-amino]-
    3-p-tolyl-propionic acid
    189 (S)-3-{[5-Methoxy-6-(4- 457.35 1.2 LC11_2 >10.0
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    190 (S)-3-[(5-Methoxy-6-o-tolyl- 403.33 1.14 LC11_2 0.0813
    pyridine-2-carbonyl)-amino]-
    3-p-tolyl-propionic acid
    191 (S)-3-{[5-Methoxy-6-(3- 419.34 1.14 LC11_2 4.57
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    192 (S)-3-{[5-Methoxy-6-(2- 457.33 1.15 LC11_2 0.1457
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    193 (S)-3-{[6-(3-Chloro-phenyl)- 425.17 1.18 LC11_2 2.74
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    194 (S)-3-{[6-(3-Fluoro-phenyl)- 407.29 1.15 LC11_2 0.725
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    195 (S)-3-[(5-Methoxy-6- 441 1.2 LC11_2 8.83
    naphthalen-2-yl-pyridine-2-
    carbonyl)-amino]-3-p-tolyl-
    propionic acid
    196 (S)-3-{[5-Methoxy-6-(2- 419.33 1.11 LC11_2 0.1191
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    197 (S)-3-[(5-Methoxy-6-m-tolyl- 404.68 1.17 LC11_2 1.71
    pyridine-2-carbonyl)-amino]-
    3-p-tolyl-propionic acid
    198 (S)-3-{[6-(2-Chloro-phenyl)- 423.24 1.14 LC11_2 0.159
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    199 (S)-3-{[6-(2-Fluoro-phenyl)- 407.28 1.12 LC11_2 0.228
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    200 (S)-3-{[6-(4-tert-Butyl- 445.39 1.25 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    201 (S)-3-{[6-(3-Cyano-phenyl)- 415.81 1.12 LC11_2 >10.0
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    202 (S)-3-{[6-(4-Cyano-phenyl)- 416.24 1.11 LC11_2 >10.0
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    203 (S)-3-{[6-(3-Acetyl-phenyl)-5- 433.31 1.1 LC11_2 8.35
    methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    204 (S)-3-[(6-Biphenyl-3-yl-5- 465.32 1.22 LC11_2 1.402
    methoxy-pyridine-2-
    carbonyl)-amino]-3-p-tolyl-
    propionic acid
    205 (S)-3-{[6-(4-Acetyl-phenyl)-5- 431.43 1.1 LC11_2 >10.0
    methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    206 (S)-3-{[6-(2,4-Difluoro- 425.26 1.14 LC11_2 0.1556
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    207 (S)-3-{[6-(3,5-Difluoro- 425.28 1.16 LC11_2 2.65
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    208 (S)-3-{[6-(3,4-Difluoro- 425.31 1.16 LC11_2 7.42
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    209 (S)-3-{[6-(2,3-Dichloro- 457.27 1.18 LC11_2 0.0696
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    210 (S)-3-{[6-(5-Acetyl-thiophen- 437.3 1.1 LC11_2 7.52
    2-yl)-5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    211 (S)-3-{[6-(2-Chloro-5- 493.24 1.19 LC11_2 0.421
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    212 (S)-3-{[6-(3-Fluoro-2-methyl- 427.27 1.13 LC11_2 0.1497
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    213 (S)-3-{[6-(2-Chloro-5- 497.2 1.17 LC11_2 0.887
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    214 (S)-3-(2-Chloro-phenyl)-3- 497.21 1.19 LC11_2 7.02
    {[6-(2-fluoro-4-
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    215 (S)-3-[(3-Methoxy- 390.2 0.88 LC11_2 9.66
    [2,4′]bipyridinyl-6-carbonyl)-
    amino]-3-p-tolyl-propionic
    acid
    216 (S)-3-[(3-Methoxy- 390.25 0.93 LC11_2 >10.0
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-p-tolyl-propionic
    acid
    217 (S)-3-{[6-(2,3-Difluoro- 425.32 1.13 LC11_2 0.0902
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    218 (S)-3-{[6-(2,5-Difluoro- 425.31 1.13 LC11_2 0.0998
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    219 (S)-3-{[6-(2,5-Dichloro- 457.25 1.18 LC11_2 0.91
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    220 (S)-3-{[6-(3,5-Dimethyl- 408.28 1.07 LC11_2 0.143
    isoxazol-4-yl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    221 (S)-3-{[6-(4-Fluoro-2-methyl- 421.35 1.15 LC11_2 0.239
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    222 (S)-3-{[6-(2,3-Dimethyl- 417.34 1.17 LC11_2 0.037
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    223 (S)-3-{[6-(3-Fluoro-4-methyl- 423.27 1.18 LC11_2 1.294
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    224 (S)-3-{[6-(2,4-Dimethyl- 417.36 1.18 LC11_2 3.39
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    225 (S)-3-{[6-(4-Fluoro-3-methyl- 421.33 1.18 LC11_2 3.26
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    226 (S)-3-[(5-Methoxy-6- 391.29 1 LC11_2 >10.0
    pyrimidin-5-yl-pyridine-2-
    carbonyl)-amino]-3-p-tolyl-
    propionic acid
    227 (S)-3-[(6′-Fluoro-3-methoxy- 408.28 1.09 LC11_2 7.63
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-p-tolyl-propionic
    acid
    228 (S)-3-{[6-(2- 462.31 1.06 LC11_2 3.96
    Dimethylcarbamoyl-phenyl)-
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    229 (S)-3-[(3,2′-Dimethoxy- 422.29 1.07 LC11_2 0.609
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-p-tolyl-propionic
    acid
    230 (S)-3-{[6-(5-Fluoro-2-methyl- 423.27 1.15 LC11_2 0.1113
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    231 (S)-3-{[6-(4-Fluoro-2- 439.27 1.12 LC11_2 0.305
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    232 (S)-3-{[6-(4-Chloro-2- 455.26 1.16 LC11_2 2.33
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    233 (S)-3-{[6-(5-Chloro-2- 455.25 1.15 LC11_2 2.24
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    234 (S)-3-{[6-(5-Fluoro-2- 439.28 1.12 LC11_2 0.51
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    235 (S)-3-{[6-(2,5-Dimethoxy- 451.3 1.1 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    236 (S)-3-{[6-(2-Fluoro-5- 477.27 1.18 LC11_2 3.57
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    237 (S)-3-{[5-Methoxy-6-(5- 395.25 1.11 LC11_2 3.54
    methyl-furan-2-yl)-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    238 (S)-3-{[5-Methoxy-6-(1- 395.26 1.02 LC11_2 >10.0
    methyl-1H-pyrazol-4-yl)-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    239 (S)-3-{[6-(2-Fluoro-5- 439.28 1.12 LC11_2 1.16
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    240 (S)-3-{[6-(5-tert-Butyl-2- 477.37 1.22 LC11_2 >10.0
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    241 (S)-3-{[6-(2-Fluoro-4- 477.27 1.19 LC11_2 >10.0
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-3-p-tolyl-
    propionic acid
    242 (S)-3-{[6-(2-Fluoro-5-methyl- 423.29 1.15 LC11_2 0.278
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    243 (S)-3-{[6-(3-Chloro-2-methyl- 439.27 1.19 LC11_2 0.2027
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    244 (S)-3-{[6-(3-Fluoro-2-methyl- 423.29 1.15 LC11_2 0.0901
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    245 (S)-3-{[6-(5-Chloro-2-fluoro- 443.24 1.17 LC11_2 0.44
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    246 (S)-3-{[6-(4-Chloro-3-fluoro- 443.22 1.2 LC11_2 4.48
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    247 (S)-3-[(2′-Chloro-3-methoxy- 440.27 1.09 LC11_2 8.43
    5′-methyl-[2,3′]bipyridinyl-6-
    carbonyl)-amino]-3-p-tolyl-
    propionic acid
    248 (S)-3-{[6-(3-Chloro-5-methyl- 439.25 1.21 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-p-tolyl-
    propionic acid
    249 (S)-3-({5-Methoxy-6-[3-(5- 473.29 1.08 LC11_2 8.71
    methyl-[1,3,4]oxadiazol-2-yl)-
    phenyl]-pyridine-2-carbonyl}-
    amino)-3-p-tolyl-propionic
    acid
    250 (S)-3-{[5-Methoxy-6-(1,3,5- 423.32 1.02 LC11_2 >10.0
    trimethyl-1H-pyrazol-4-yl)-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    251 (S)-3-{[5-Methoxy-6-(1- 444.31 1.16 LC11_2 8.94
    methyl-1H-indol-6-yl)-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    252 (S)-3-{[6-(4-Chloro-3- 455.26 1.18 LC11_2 >10.0
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    253 (S)-3-(2-Fluoro-phenyl)-3- 461.3 1.17 LC11_2 4.06
    {[5-methoxy-6-(3-
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    254 (S)-3-(2-Fluoro-phenyl)-3- 395.25 1.11 LC11_2 0.1818
    [(5-methoxy-6-phenyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    255 (S)-3-{[6-(2,4-Dichloro- 463.18 1.18 LC11_2 0.879
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    256 (S)-3-{[6-(3-Chloro-4-fluoro- 447.21 1.17 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    257 (S)-3-(2-Fluoro-phenyl)-3- 413.21 1.12 LC11_2 1.263
    {[6-(4-fluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    258 (S)-3-{[6-(4-Chloro-phenyl)- 429.24 1.17 LC11_2 5.27
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    259 (S)-3-(2-Fluoro-phenyl)-3- 425.27 1.11 LC11_2 5.01
    {[5-methoxy-6-(4-methoxy-
    phenyl)-pyridine-2-carbonyl]-
    amino}-propionic acid
    260 (S)-3-(2-Fluoro-phenyl)-3- 409.27 1.15 LC11_2 5.18
    [(5-methoxy-6-p-tolyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    261 (S)-3-(2-Fluoro-phenyl)-3- 463.27 1.18 LC11_2 >10.0
    {[5-methoxy-6-(4-
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    262 (S)-3-(2-Fluoro-phenyl)-3- 407.26 1.12 LC11_2 0.0819
    [(5-methoxy-6-o-tolyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    263 (S)-3-(2-Fluoro-phenyl)-3- 425.27 1.11 LC11_2 5.06
    {[5-methoxy-6-(3-methoxy-
    phenyl)-pyridine-2-carbonyl]-
    amino}-propionic acid
    264 (S)-3-(2-Fluoro-phenyl)-3- 463.25 1.12 LC11_2 0.179
    {[5-methoxy-6-(2-
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    265 (S)-3-{[6-(3-Chloro-phenyl)- 429.23 1.16 LC11_2 1.719
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    266 (S)-3-(2-Fluoro-phenyl)-3- 413.23 1.13 LC11_2 1.26
    {[6-(3-fluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    267 (S)-3-(2-Fluoro-phenyl)-3- 445.3 1.18 LC11_2 >10.0
    [(5-methoxy-6-naphthalen-2-
    yl-pyridine-2-carbonyl)-
    amino]-propionic acid
    268 (S)-3-(2-Fluoro-phenyl)-3- 425.25 1.08 LC11_2 0.102
    {[5-methoxy-6-(2-methoxy-
    phenyl)-pyridine-2-carbonyl]-
    amino}-propionic acid
    269 (S)-3-(2-Fluoro-phenyl)-3- 409.26 1.15 LC11_2 1.015
    [(5-methoxy-6-m-tolyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    270 (S)-3-{[6-(2-Chloro-phenyl)- 429.23 1.11 LC11_2 0.9178
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    271 (S)-3-(2-Fluoro-phenyl)-3- 413.23 1.1 LC11_2 0.0418
    {[6-(2-fluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    272 (S)-3-{[6-(4-tert-Butyl- 451.34 1.23 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    273 (S)-3-{[6-(3-Cyano-phenyl)- 420.25 1.09 LC11_2 9.57
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    274 (S)-3-{[6-(4-Cyano-phenyl)- 420.23 1.09 LC11_2 >10.0
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    275 (S)-3-{[6-(3-Acetyl-phenyl)-5- 437.25 1.08 LC11_2 8.54
    methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    276 (S)-3-[(6-Biphenyl-3-yl-5- 471.33 1.21 LC11_2 2.16
    methoxy-pyridine-2-
    carbonyl)-amino]-3-(2-fluoro-
    phenyl)-propionic acid
    277 (S)-3-{[6-(4-Acetyl-phenyl)-5- 437.27 1.07 LC11_2 >10.0
    methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    278 (S)-3-{[6-(2,4-Difluoro- 431.24 1.12 LC11_2 0.1201
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    279 (S)-3-{[6-(3,5-Difluoro- 431.21 1.15 LC11_2 3.85
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    280 (S)-3-{[6-(3,4-Difluoro- 431.23 1.14 LC11_2 3.12
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    281 (S)-3-{[6-(2,3-Dichloro- 463.16 1.15 LC11_2 0.114
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    282 (S)-3-(2-Fluoro-phenyl)-3- 396.21 0.84 LC11_2 >10.0
    [(3-methoxy-[2,4′]bipyridinyl-
    6-carbonyl)-amino]-propionic
    acid
    283 (S)-3-{[6-(5-Cyano-thiophen- 426.15 1.1 LC11_2 5.4
    2-yl)-5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    284 (S)-3-(2-Fluoro-phenyl)-3- 396.22 0.88 LC11_2 >10.0
    [(3-methoxy-[2,3′]bipyridinyl-
    6-carbonyl)-amino]-propionic
    acid
    285 (S)-3-{[6-(2,3-Difluoro- 431.25 1.11 LC11_2 0.234
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    286 (S)-3-{[6-(2,5-Difluoro- 431.23 1.11 LC11_2 0.171
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    287 (S)-3-{[6-(3,5-Dimethyl- 414.25 1.04 LC11_2 0.645
    isoxazol-4-yl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    288 (S)-3-{[6-(4-Fluoro-2-methyl- 427.27 1.13 LC11_2 0.394
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    289 (S)-3-{[6-(2,3-Dimethyl- 423.29 1.14 LC11_2 0.0528
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    290 (S)-3-{[6-(3-Fluoro-4-methyl- 427.26 1.16 LC11_2 3.81
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    291 (S)-3-{[6-(2,4-Dimethyl- 423.29 1.15 LC11_2 4.02
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    292 (S)-3-{[6-(4-Fluoro-3-methyl- 427.25 1.16 LC11_2 4.13
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    293 (S)-3-(2-Fluoro-phenyl)-3- 397.2 0.96 LC11_2 >10.0
    [(5-methoxy-6-pyrimidin-5-yl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    294 (S)-3-[(6′-Fluoro-3-methoxy- 414.22 1.06 LC11_2 >10.0
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-(2-fluoro-phenyl)-
    propionic acid
    295 (S)-3-{[6-(2- 464.38 1.02 LC11_2 4.51
    Dimethylcarbamoyl-phenyl)-
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-fluoro-
    phenyl)-propionic acid
    296 (S)-3-[(3,2′-Dimethoxy- 426.26 1.04 LC11_2 0.756
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-(2-fluoro-phenyl)-
    propionic acid
    297 (S)-3-{[6-(5-Fluoro-2-methyl- 427.25 1.13 LC11_2 0.475
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    298 (S)-3-{[6-(4-Fluoro-2- 443.26 1.1 LC11_2 0.389
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    299 (S)-3-{[6-(4-Chloro-2- 459.24 1.14 LC11_2 1.83
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    300 (S)-3-{[6-(5-Chloro-2- 459.25 1.13 LC11_2 4.11
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    301 (S)-3-{[6-(5-Fluoro-2- 443.26 1.1 LC11_2 0.0737
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    302 (S)-3-(2-Fluoro-phenyl)-3- 448.3 1.12 LC11_2 >10.0
    {[5-methoxy-6-(1-methyl-1H-
    indol-5-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    303 (S)-3-{[6-(2,5-Dimethoxy- 455.29 1.08 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    304 (S)-3-(2-Fluoro-phenyl)-3- 481.23 1.16 LC11_2 3.99
    {[6-(2-fluoro-5-
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    305 (S)-3-(2-Fluoro-phenyl)-3- 399.23 1.09 LC11_2 >10.0
    {[5-methoxy-6-(5-methyl-
    furan-2-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    306 (S)-3-(2-Fluoro-phenyl)-3- 399.22 0.99 LC11_2 >10.0
    {[5-methoxy-6-(1-methyl-1H-
    pyrazol-4-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    307 (S)-3-{[6-(2-Fluoro-5- 443.26 1.1 LC11_2 2.92
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    308 (S)-3-{[6-(5-tert-Butyl-2- 481.44 1.2 LC11_2 >10.0
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    309 (S)-3-(2-Fluoro-phenyl)-3- 481.25 1.17 LC11_2 >10.0
    {[6-(2-fluoro-4-
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    310 (S)-3-{[6-(2-Fluoro-5-methyl- 427.26 1.13 LC11_2 0.262
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    311 (S)-3-{[6-(3-Chloro-2-methyl- 443.25 1.16 LC11_2 0.2019
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    312 (S)-3-{[6-(5-Chloro-2-fluoro- 447.19 1.14 LC11_2 0.481
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    313 (S)-3-{[6-(4-Chloro-3-fluoro- 447.21 1.18 LC11_2 3.55
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    314 (S)-3-[(2′-Chloro-3-methoxy- 444.23 1.06 LC11_2 >10.0
    5′-methyl-[2,3′]bipyridinyl-6-
    carbonyl)-amino]-3-(2-fluoro-
    phenyl)-propionic acid
    315 (S)-3-{[6-(3-Chloro-5-methyl- 443.25 1.19 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    316 (S)-3-(2-Fluoro-phenyl)-3- 477.31 1.06 LC11_2 >10.0
    ({5-methoxy-6-[3-(5-methyl-
    [1,3,4]oxadiazol-2-yl)-
    phenyl]-pyridine-2-carbonyl}-
    amino)-propionic acid
    317 (S)-3-(2-Fluoro-phenyl)-3- 427.27 0.99 LC11_2 >10.0
    {[5-methoxy-6-(1,3,5-
    trimethyl-1H-pyrazol-4-yl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    318 (S)-3-(2-Fluoro-phenyl)-3- 448.3 1.13 LC11_2 >10.0
    {[5-methoxy-6-(1-methyl-1H-
    indol-6-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    319 (S)-3-{[6-(4-Chloro-3- 459.22 1.16 LC11_2 >10.0
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    320 (S)-3-{[6-(3-Chloro-2-fluoro- 447.22 1.14 LC11_2 0.0484
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    321 (S)-3-(2-Fluoro-phenyl)-3- 481.33 0.91 LC11_2 >10.0
    [(3-methoxy-2′-morpholin-4-
    yl-[2,4′]bipyridinyl-6-
    carbonyl)-amino]-propionic
    acid
    322 (S)-3-(2-Fluoro-phenyl)-3- 399.21 1.11 LC11_2 0.0813
    {[5-methoxy-6-(2-methyl-
    furan-3-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    323 (S)-3-{[6-(2-Chloro-5-methyl- 443.18 1.14 LC11_2 2.31
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    324 (S)-3-{[6-(2-Chloro-3-fluoro- 447.2 1.12 LC11_2 1.266
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    325 (S)-3-{[6-(4-Cyano-2-fluoro- 438.23 1.08 LC11_2 3.58
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    326 (S)-3-(2-Fluoro-phenyl)-3- 467.29 1 LC11_2 8.46
    ({6-[3-(3-hydroxy-oxetan-3-
    yl)-phenyl]-5-methoxy-
    pyridine-2-carbonyl}-amino)-
    propionic acid
    327 (S)-3-(2-Fluoro-phenyl)-3- 453.32 1.07 LC11_2 7.32
    ({6-[3-(1-hydroxy-1-methyl-
    ethyl)-phenyl]-5-methoxy-
    pyridine-2-carbonyl}-amino)-
    propionic acid
    328 (S)-3-{[6-(2-Chloro-3-methyl- 443.24 1.14 LC11_2 0.1192
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    fluoro-phenyl)-propionic acid
    329 (S)-3-(2-Chloro-phenyl)-3- 479.11 1.21 LC11_3 3.74
    {[5-methoxy-6-(3-
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    330 (S)-3-(2-Chloro-phenyl)-3- 411.12 1.14 LC11_3 0.0751
    [(5-methoxy-6-phenyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    331 (S)-3-(2-Chloro-phenyl)-3- 479.05 1.21 LC11_3 0.589
    {[6-(2,4-dichloro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    332 (S)-3-{[6-(3-Chloro-4-fluoro- 463.07 1.2 LC11_3 5.24
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    333 (S)-3-(2-Chloro-phenyl)-3- 429.12 1.16 LC11_3 0.909
    {[6-(4-fluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    334 (S)-3-(2-Chloro-phenyl)-3- 445.09 1.2 LC11_3 1.81
    {[6-(4-chloro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    335 (S)-3-(2-Chloro-phenyl)-3- 441.13 1.14 LC11_3 2.25
    {[5-methoxy-6-(4-methoxy-
    phenyl)-pyridine-2-carbonyl]-
    amino}-propionic acid
    336 (S)-3-(2-Chloro-phenyl)-3- 425.14 1.18 LC11_3 3.13
    [(5-methoxy-6-p-tolyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    337 (S)-3-(2-Chloro-phenyl)-3- 479.11 1.21 LC11_3 9.5
    {[5-methoxy-6-(4-
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    338 (S)-3-(2-Chloro-phenyl)-3- 425.14 1.15 LC11_3 >10.0
    [(5-methoxy-6-o-tolyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    339 (S)-3-(2-Chloro-phenyl)-3- 441.13 1.14 LC11_3 2.78
    {[5-methoxy-6-(3-methoxy-
    phenyl)-pyridine-2-carbonyl]-
    amino}-propionic acid
    340 (S)-3-(2-Chloro-phenyl)-3- 445.09 1.19 LC11_3 1.51
    {[6-(3-chloro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    341 (S)-3-(2-Chloro-phenyl)-3- 429.22 1.13 LC11_2 9.86
    {[5-(3-fluoro-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    342 (S)-3-{[6-Methoxy-5-(4- 459.27 1.18 LC11_2 >10.0
    trifluoromethyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    343 (S)-3-(2-Chloro-phenyl)-3- 479.22 1.18 LC11_2 >10.0
    {[6-methoxy-5-(3-
    trifluoromethyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    propionic acid
    344 (S)-3-(2-Chloro-phenyl)-3- 411.23 1.12 LC11_2 3.49
    [(6-methoxy-5-phenyl-
    pyridine-3-carbonyl)-amino]-
    propionic acid
    345 (S)-3-{[5-(3-Chloro-4-fluoro- 463.16 1.17 LC11_2 >10.0
    phenyl)-6-methoxy-pyridine-
    3-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    346 (S)-3-(2-Chloro-phenyl)-3- 429.2 1.13 LC11_2 8.26
    {[5-(4-fluoro-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    347 (S)-3-{[5-Methoxy-6-(3- 459.08 1.19 LC11_2 0.981
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    348 (S)-3-{[6-(2,4-Dichloro- 459.01 1.19 LC11_2 0.161
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino)-3-o-tolyl-
    propionic acid
    349 (S)-3-{[6-(3-Chloro-4-fluoro- 443.03 1.19 LC11_2 1.458
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    350 (S)-3-{[6-(4-Fluoro-phenyl)- 409.08 1.14 LC11_2 0.267
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    351 (S)-3-{[6-(4-Chloro-phenyl)- 425.04 1.18 LC11_2 0.501
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    352 (S)-3-[(5-Methoxy-6-p-tolyl- 405.12 1.17 LC11_2 0.586
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    353 (S)-3-{[5-Methoxy-6-(4- 459.08 1.19 LC11_2 >10.0
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    354 (S)-3-{[6-(3-Chloro-phenyl)- 425.05 1.18 LC11_2 0.53
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    355 (S)-3-{[5-Methoxy-6-(2- 421.13 1.1 LC11_2 0.0833
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    356 (S)-3-[(5-Methoxy-6-m-tolyl- 405.09 1.16 LC11_2 0.152
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    357 (S)-3-{[6-(2-Chloro-phenyl)- 425.06 1.13 LC11_2 0.223
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    358 (S)-3-{[6-(4-tert-Butyl- 447.19 1.25 LC11_2 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    359 (S)-3-{[6-(3-Cyano-phenyl)- 416.1 1.11 LC11_2 4.49
    5-methoxy-pyridine-2-
    carbonyl]amino}-3-o-tolyl-
    propionic acid
    360 (S)-3-{[6-(3-Acetyl-phenyl)-5- 433.13 1.1 LC11_2 2.42
    methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    361 (S)-3-{[6-(4-Acetyl-phenyl)-5- 433.12 1.09 LC11_2 9.24
    methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    362 (S)-3-{[6-(3,5-Difluoro- 427.08 1.16 LC11_2 1.43
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    363 (S)-3-{[6-(3,4-Difluoro- 427.11 1.16 LC11_2 0.258
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    364 (S)-3-([6-(5-Acetyl-thiophen- 439.09 1.1 LC11_2 9.25
    2-yl)-5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    365 (S)-3-[(3-Methoxy- 392.13 0.87 LC11_2 5.45
    [2,4′]bipyridinyl-6-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    366 (S)-3-{[6-(2,5-Difluoro- 427.09 1.13 LC11_2 0.121
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    367 (S)-3-{[6-(2,5-Dichloro- 459.01 1.18 LC11_2 0.385
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    368 (S)-3-{[6-(3,5-Dimethyl- 410.24 4 LC2 0.1873
    isoxazol-4-yl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    369 (S)-3-{[6-(2,3-Dimethyl- 419.14 1.16 LC11_2 0.1318
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    370 (S)-3-{[6-(3-Fluoro-4-methyl- 423.11 1.18 LC11_2 1.585
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    371 (S)-3-{[6-(2,4-Dimethyl- 419.16 1.17 LC11_2 0.457
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    372 (S)-3-[(5-Methoxy-6- 393.11 0.98 LC11_2 8.88
    pyrimidin-5-yl-pyridine-2-
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    373 (S)-3-[(6′-Fluoro-3-methoxy- 410.1 1.08 LC11_2 1.6
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    374 (S)-3-{[6-(2- 460.12 1.04 LC11_2 2.48
    Dimethylcarbamoyl-phenyl)-
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    375 (S)-3-{[6-(4-Fluoro-2- 439.13 1.12 LC11_2 0.216
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    376 (S)-3-{[5-Methoxy-6-(5- 395.11 1.11 LC11_2 6.1
    methyl-furan-2-yl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    377 (S)-3-{[5-Methoxy-6-(1- 395.13 1.01 LC11_2 >10.0
    methyl-1H-pyrazol-4-yl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    378 (S)-3-{[6-(3-Chloro-5-methyl- 439.1 1.21 LC11_2 7.49
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    379 (S)-3-{[5-Methoxy-6-(1,3,5- 421.13 1 LC11_2 >10.0
    trimethyl-1H-pyrazol-4-yl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    380 (S)-3-{[5-Methoxy-6-(1- 444.15 1.15 LC11_2 5.33
    methyl-1H-indol-6-yl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    381 (S)-3-[(3-Methoxy-2′- 477.16 0.93 LC11_2 >10.0
    morpholin-4-yl-
    [2,4′]bipyridinyl-6-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    382 (S)-3-{[6-(2-Chloro-5-methyl- 439.13 1.16 LC11_2 0.497
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    383 (S)-3-{[6-(2-Chloro-3-fluoro- 443.06 1.14 LC11_2 1.635
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    384 (S)-3-({6-[3-(3-Hydroxy- 463.15 1.02 LC11_2 2.39
    oxetan-3-yl)-phenyl]-5-
    methoxy-pyridine-2-
    carbonyl}-amino)-3-o-tolyl-
    propionic acid
    385 (S)-3-({6-[3-(1-Hydroxy-1- 449.17 1.08 LC11_2 1.15
    methyl-ethyl)-phenyl]-5-
    methoxy-pyridine-2-
    carbonyl}-amino)-3-o-tolyl-
    propionic acid
    386 (S)-3-(2-Chloro-phenyl)-3- 445.17 1.17 LC11_2 10.4
    {[5-(4-chloro-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    387 (S)-3-(2-Chloro-phenyl)-3- 441.24 1.11 LC11_2 9.43
    {[6-methoxy-5-(4-methoxy-
    phenyl)-pyridine-3-carbonyl]-
    amino}-propionic acid
    388 (S)-3-(2-Chloro-phenyl)-3- 425.24 1.15 LC11_2 7.12
    [(6-methoxy-5-p-tolyl-
    pyridine-3-carbonyl)-amino]-
    propionic acid
    389 (S)-3-(2-Chloro-phenyl)-3- 479.21 1.18 LC11_2 >10.0
    {[6-methoxy-5-(4-
    trifluoromethyl-phenyl)-
    pyridine-3-carbonyl]-amino}-
    propionic acid
    390 (S)-3-(2-Chloro-phenyl)-3- 425.25 1.13 LC11_2 0.702
    [(6-methoxy-5-o-tolyl-
    pyridine-3-carbonyl)-amino]-
    propionic acid
    391 (S)-3-(2-Chloro-phenyl)-3- 441.24 1.12 LC11_2 10.6
    {[6-methoxy-5-(3-methoxy-
    phenyl)-pyridine-3-carbonyl]-
    amino}-propionic acid
    392 (S)-3-(2-Chloro-phenyl)-3- 445.2 1.16 LC11_2 10.3
    {[5-(3-choro-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    393 (S)-3-(2-Chloro-phenyl)-3- 461.25 1.18 LC11_2 >10.0
    [(6-methoxy-5-naphthalen-2-
    yl-pyridine-3-carbonyl)-
    amino]-propionic acid
    394 (S)-3-(2-Chloro-phenyl)-3- 441.25 1.1 LC11_2 3.76
    {[6-methoxy-5-(2-methoxy-
    phenyl)-pyridine-3-carbonyl]-
    amino}-propionic acid
    395 (S)-3-(2-Chloro-phenyl)-3- 425.24 1.15 LC11_2 6.57
    [(6-methoxy-5-m-tolyl-
    pyridine-3-carbonyl)-amino]-
    propionic acid
    396 (S)-3-{[5-(4-tert-Butyl- 467.31 1.24 LC11_2 >10.0
    phenyl)-6-methoxy-pyridine-
    3-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    397 (S)-3-(2-Chloro-phenyl)-3- 436.23 1.09 LC11_2 >10.0
    {[5-(3-cyano-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    398 (S)-3-(2-Chloro-phenyl)-3- 436.23 1.09 LC11_2 >10.0
    {[5-(4-cyano-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    399 (S)-3-{[5-(3-Acetyl-phenyl)-6- 453.25 1.08 LC11_2 >10.0
    methoxy-pyridine-3-
    carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    400 (S)-3-[(5-Biphenyl-3-yl-6- 487.27 1.21 LC11_2 >10.0
    methoxy-pyridine-3-
    carbonyl)-amino]-3-(2-
    chloro-phenyl)-propionic acid
    401 (S)-3-{[5-(4-Acetyl-phenyl)-6- 453.25 1.08 LC11_2 >10.0
    methoxy-pyridine-3-
    carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    402 (S)-3-(2-Chloro-phenyl)-3- 447.2 1.15 LC11_2 >10.0
    {[5-(3,5-difluoro-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    403 (S)-3-(2-Chloro-phenyl)-3- 447.2 1.14 LC11_2 >10.0
    {[5-(3,4-difluoro-phenyl)-6-
    methoxy-pyridine-3-
    carbonyl]-amino}-propionic
    acid
    404 (S)-3-(2-Chloro-phenyl)-3- 443.26 1.14 LC11_2 7.14
    {[5-(4-fluoro-2-methyl-
    phenyl)-6-methoxy-pyridine-
    3-carbonyl]-amino}-propionic
    acid
    405 (S)-3-[(6-Methoxy-5-phenyl- 391.28 1.12 LC11_2 3.9
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    406 (S)-3-{[5-(3-Chloro-4-fluoro- 443.22 1.17 LC11_2 10
    phenyl)-6-methoxy-pyridine-
    3-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    407 (S)-3-{[5-(4-Fluoro-phenyl)- 409.24 1.13 LC11_2 4.39
    6-methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    408 (S)-3-{[5-(4-Chloro-phenyl)- 425.22 1.17 LC11_2 5.73
    6-methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    409 (S)-3-{[6-Methoxy-5-(4- 421.3 1.11 LC11_2 9.04
    methoxy-phenyl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    410 (S)-3-[(6-Methoxy-5-p-tolyl- 405.26 1.15 LC11_2 5.38
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    411 (S)-3-[(6-Methoxy-5-o-tolyl- 405.27 1.13 LC11_2 1.186
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    412 (S)-3-{[6-Methoxy-5-(3- 421.27 1.12 LC11_2 8.36
    methoxy-phenyl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    413 (S)-3-{[5-(3-Chloro-phenyl)- 425.21 1.16 LC11_2 6.24
    6-methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    414 (S)-3-{[5-(3-Fluoro-phenyl)- 409.22 1.13 LC11_2 8.07
    6-methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    415 (S)-3-[(6-Methoxy-5- 441.33 1.18 LC11_2 >10.0
    naphthalen-2-yl-pyridine-3-
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    416 (S)-3-{[6-Methoxy-5-(2- 421.31 1.1 LC11_2 3.42
    methoxy-phenyl)-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    417 (S)-3-[(6-Methoxy-5-m-tolyl- 405.28 1.15 LC11_2 4.86
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    418 (S)-3-{[5-(2-Fluoro-phenyl)- 409.23 1.11 LC11_2 1.083
    6-methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    419 (S)-3-{[5-(4-tert-Butyl- 447.38 1.24 LC11_2 >10.0
    phenyl)-6-methoxy-pyridine-
    3-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    420 (S)-3-{[5-(3-Cyano-phenyl)- 416.25 1.09 LC11_2 >10.0
    6-methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    421 (S)-3-{[5-(4-Cyano-phenyl)- 416.29 1.09 LC11_2 10.4
    6-methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    422 (S)-3-{[5-(3-Acetyl-phenyl)-6- 433.28 1.08 LC11_2 >10.0
    methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    423 (S)-3-[(5-Biphenyl-3-yl-6- 467.34 1.21 LC11_2 >10.0
    methoxy-pyridine-3-
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    424 (S)-3-{[5-(4-Acetyl-phenyl)-6- 433.28 1.08 LC11_2 >10.0
    methoxy-pyridine-3-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    425 (S)-3-{[5-(3,4-Difluoro- 427.25 1.15 LC11_2 8.84
    phenyl)-6-methoxy-pyridine-
    3-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    426 (S)-3-(2-Chloro-phenyl)-3- 429.12 1.16 LC11_3 1.54
    {[6-(3-fluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    427 (S)-3-(2-Chloro-phenyl)-3- 461.14 1.21 LC11_3 7.11
    [(5-methoxy-6-naphthalen-2-
    yl-pyridine-2-carbonyl)-
    amino]-propionic acid
    428 (S)-3-(2-Chloro-phenyl)-3- 441.14 1.11 LC11_3 0.1161
    {[5-methoxy-6-(2-methoxy-
    phenyl)-pyridine-2-carbonyl]-
    amino}-propionic acid
    429 (S)-3-(2-Chloro-phenyl)-3- 425.14 1.18 LC11_3 0.335
    [(5-methoxy-6-m-tolyl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    430 (S)-3-(2-Chloro-phenyl)-3- 445.09 1.14 LC11_3 0.147
    {[6-(2-chloro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    431 (S)-3-(2-Chloro-phenyl)-3- 429.11 1.13 LC11_3 0.132
    {[6-(2-fluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    432 (S)-3-{[6-(4-tert-Butyl- 467.18 1.26 LC11_3 >10.0
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    433 (S)-3-(2-Chloro-phenyl)-3- 436.12 1.12 LC11_3 8.26
    {[6-(3-cyano-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    434 (S)-3-(2-Chloro-phenyl)-3- 436.12 1.12 LC11_3 >10.0
    {[6-(4-cyano-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    435 (S)-3-{[6-(3-Acetyl-phenyl)-5- 453.13 1.11 LC11_3 4.2
    methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    436 (S)-3-[(6-Biphenyl-3-yl-5- 487.16 1.24 LC11_3 2.97
    methoxy-pyridine-2-
    carbonyl)-amino]-3-(2-
    chloro-phenyl)-propionic acid
    437 (S)-3-{[6-(4-Acetyl-phenyl)-5- 453.13 1.1 LC11_3 >10.0
    methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    438 (S)-3-(2-Chloro-phenyl)-3- 447.19 1.13 LC11_2 0.0491
    {[6-(2,4-difluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    439 (S)-3-(2-Chloro-phenyl)-3- 447.11 1.18 LC11_3 2.39
    {[6-(3,5-difluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    440 (S)-3-(2-Chloro-phenyl)-3- 447.11 1.17 LC11_3 1.96
    {[6-(3,4-difluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    441 (S)-3-(2-Chloro-phenyl)-3- 479.05 1.18 LC11_3 0.2352
    {[6-(2,3-dichloro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    442 (S)-3-{[6-(5-Acetyl-thiophen- 459.09 1.11 LC11_3 >10.0
    2-yl)-5-methoxy-pyridine-2-
    carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    443 (S)-3-(2-Chloro-phenyl)-3- 412.12 0.86 LC11_3 8.04
    [(3-methoxy-[2,4′]bipyridinyl-
    6-carbonyl)-amino]-propionic
    acid
    444 (S)-3-(2-Chloro-phenyl)-3- 412.12 0.91 LC11_3 10.1
    [(3-methoxy-[2,3′]bipyridinyl-
    6-carbonyl)-amino]-propionic
    acid
    445 (S)-3-(2-Chloro-phenyl)-3- 447.11 1.14 LC11_3 0.1505
    {[6-(2,3-difluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    446 (S)-3-(2-Chloro-phenyl)-3- 447.1 1.14 LC11_3 0.0571
    {[6-(2,5-difluoro-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    447 (S)-3-(2-Chloro-phenyl)-3- 443.13 1.16 LC11_3 0.1106
    {[6-(4-fluoro-2-methyl-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    448 (S)-3-(2-Chloro-phenyl)-3- 439.15 1.17 LC11_3 0.1393
    {[6-(2,3-dimethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    449 (S)-3-(2-Chloro-phenyl)-3- 443.13 1.2 LC11_3 2.016
    {[6-(3-fluoro-4-methyl-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    450 (S)-3-(2-Chloro-phenyl)-3- 439.15 1.18 LC11_3 1.6
    {[6-(2,4-dimethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    451 (S)-3-(2-Chloro-phenyl)-3- 443.13 1.19 LC11_3 3.79
    {[6-(4-fluoro-3-methyl-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    452 (S)-3-(2-Chloro-phenyl)-3- 413.11 0.99 LC11_3 >10.0
    [(5-methoxy-6-pyrimidin-5-yl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    453 (S)-3-(2-Chloro-phenyl)-3- 430.11 1.09 LC11_3 6.49
    [(6′-fluoro-3-methoxy-
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-propionic acid
    454 (S)-3-(2-Chloro-phenyl)-3- 482.3 1.04 LC11_2 2.5
    {[6-(2-dimethylcarbamoyl-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    455 (S)-3-(2-Chloro-phenyl)-3- 442.13 1.07 LC11_3 0.185
    [(3,2′-dimethoxy-
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-propionic acid
    456 (S)-3-(2-Chloro-phenyl)-3- 443.13 1.16 LC11_3 0.1193
    {[6-(5-fluoro-2-methyl-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    457 (S)-3-(2-Chloro-phenyl)-3- 459.13 1.13 LC11_3 0.1072
    {[6-(4-fluoro-2-methoxy-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    458 (S)-3-{[6-(4-Chloro-2- 475.1 1.17 LC11_3 0.415
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-chloro-phenyl)-propionic
    acid
    459 (S)-3-{[6-(5-Chloro-2- 475.1 1.16 LC11_3 1.147
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-chloro-phenyl)-propionic
    acid
    460 (S)-3-(2-Chloro-phenyl)-3- 459.12 1.12 LC11_3 0.1073
    {[6-(5-fluoro-2-methoxy-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    461 (S)-3-(2-Chloro-phenyl)-3- 471.14 1.11 LC11_3 8.31
    {[6-(2,5-dimethoxy-phenyl)-
    5-methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    462 (S)-3-(2-Chloro-phenyl)-3- 497.2 1.18 LC11_2 0.597
    {[6-(2-fluoro-5-
    trifluoromethyl-phenyl)-5-
    methoxy-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    463 (S)-3-(2-Chloro-phenyl)-3- 415.15 1.11 LC11_2 >10.0
    {[5-methoxy-6-(5-methyl-
    furan-2-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    464 (S)-3-{[5-Methoxy-6-(2- 459.1 1.14 LC11_2 0.0993
    trifluoromethyl-phenyl)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    465 (S)-3-{[6-(4-Cyano-phenyl)- 416.1 1.1 LC11_2 6.8
    5-methoxy-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    466 (S)-3-{[6-(2,4-Difluoro- 427.09 1.13 LC11_2 0.0463
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    467 (S)-3-{[6-(4-Fluoro-2-methyl- 423.09 1.14 LC11_2 0.1768
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    468 (S)-3-[(3,2′-Dimethoxy- 422.12 1.06 LC11_2 0.347
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    469 (S)-3-[(2′-Chloro-3-methoxy- 440.1 1.08 LC11_2 5.63
    5′-methyl-[2,3′]bipyridinyl-6-
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    470 (S)-3-[(3′-Fluoro-3-methoxy- 410.06 1.06 LC11_2 0.1182
    [2,4′]bipyridinyl-6-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    471 (S)-3-({5-Methoxy-6-[3-(5- 473.13 1.07 LC11_2 4.23
    methyl-[1,3,4]oxadiazol-2-yl)-
    phenyl]-pyridine-2-carbonyl}-
    amino)-3-o-tolyl-propionic
    acid
    472 (S)-3-{[5-Methoxy-6-(2- 395.04 1.13 LC11_2 0.096
    methyl-furan-3-yl)-pyridine-2-
    carbonyl]-amino}-3-o-tolyl-
    propionic acid
    473 (S)-3-{[6-(4-Cyano-2-fluoro- 434.13 1.1 LC11_2 0.288
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-o-tolyl-
    propionic acid
    474 (S)-3-(2-Chloro-phenyl)-3- 459.12 1.13 LC11_3 0.58
    {[6-(2-fluoro-5-methoxy-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    475 (S)-3-{[6-(5-tert-Butyl-2- 497.2 1.23 LC11_3 >10.0
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-chloro-phenyl)-propionic
    acid
    476 (S)-3-(2-Chloro-phenyl)-3- 443.13 1.16 LC11_3 0.3695
    {[6-(2-fluoro-5-methyl-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    477 (S)-3-{[6-(3-Chloro-2-methyl- 459.1 1.19 LC11_3 0.11
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    478 (S)-3-(2-Chloro-phenyl)-3- 443.13 1.16 LC11_3 0.192
    {[6-(3-fluoro-2-methyl-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    479 (S)-3-{[6-(5-Chloro-2-fluoro- 463.08 1.17 LC11_3 0.262
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    480 (S)-3-{[6-(4-Chloro-3-fluoro- 463.07 1.21 LC11_3 4.37
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    481 (S)-3-[(2′-Chloro-3-methoxy- 460.1 1.09 LC11_3 8.77
    5′-methyl-[2,3′]bipyridinyl-6-
    carbonyl)-amino]-3-(2-
    chloro-phenyl)-propionic acid
    482 (S)-3-(2-Chloro-phenyl)-3- 430.2 1.03 LC11_2 0.1153
    [(3′-fluoro-3-methoxy-
    [2,4′]bipyridinyl-6-carbonyl)-
    amino]-propionic acid
    483 (S)-3-{[6-(3-Chloro-5-methyl- 459.1 1.22 LC11_3 9.49
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    484 (S)-3-(2-Chloro-phenyl)-3- 493.14 1.09 LC11_3 6.69
    ({5-methoxy-6-[3-(5-methyl-
    [1,3,4]oxadiazol-2-yl)-
    phenyl]-pyridine-2-carbonyl}-
    amino)-propionic acid
    485 (S)-3-(2-Chloro-phenyl)-3- 413 1.07 LC11_3 0.1588
    [(5-methoxy-6-pyrazin-2-yl-
    pyridine-2-carbonyl)-amino]-
    propionic acid
    486 (S)-3-(2-Chloro-phenyl)-3- 443.16 1.02 LC11_3 4.95
    {[5-methoxy-6-(1,3,5-
    trimethyl-1H-pyrazol-4-yl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    487 (S)-3-(2-Chloro-phenyl)-3- 464.15 1.17 LC11_3 >10.0
    {[5-methoxy-6-(1-methyl-1H-
    indol-6-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    488 (S)-3-{[6-(4-Chloro-3- 475.09 1.19 LC11_3 >10.0
    methoxy-phenyl)-5-methoxy-
    pyridine-2-carbonyl]-amino}-
    3-(2-chloro-phenyl)-propionic
    acid
    489 (S)-3-{[6-(3-Chloro-2-fluoro- 463.08 1.17 LC11_3 0.1314
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    490 (S)-3-(2-Chloro-phenyl)-3- 497.17 0.92 LC11_3 9.08
    [(3-methoxy-2′-morpholin-4-
    yl-[2,4′]bipyridinyl-6-
    carbonyl)-amino]-propionic
    acid
    491 (S)-3-(2-Chloro-phenyl)-3- 415.12 1.14 LC11_3 0.199
    {[5-methoxy-6-(2-methyl-
    furan-3-yl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    492 (S)-3-{[6-(2-Chloro-5-methyl- 459.1 1.17 LC11_3 1.053
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    493 (S)-3-{[6-(2-Chloro-3-fluoro- 463.07 1.15 LC11_3 0.05065
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    494 (S)-3-(2-Chloro-phenyl)-3- 454.11 1.11 LC11_3 11.4
    {[6-(4-cyano-2-fluoro-
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-propionic
    acid
    495 (S)-3-(2-Chloro-phenyl)-3- 483.14 1.04 LC11_3 3.89
    ({6-[3-(3-hydroxy-oxetan-3-
    yl)-phenyl]-5-methoxy-
    pyridine-2-carbonyl}-amino)-
    propionic acid
    496 (S)-3-(2-Chloro-phenyl)-3- 469.16 1.1 LC11_3 2.86
    ({6-[3-(1-hydroxy-1-methyl-
    ethyl)-phenyl]-5-methoxy-
    pyridine-2-carbonyl}-amino)-
    propionic acid
    497 (S)-3-{[6-(2-Chloro-3-methyl- 459.1 1.17 LC11_3 0.0678
    phenyl)-5-methoxy-pyridine-
    2-carbonyl]-amino}-3-(2-
    chloro-phenyl)-propionic acid
    498 3-Biphenyl-4-yl-3-[(3,6- 413.24 1.13 LC11_2 8.55
    dichloro-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    499 3-Biphenyl-4-yl-3-[(4-chloro- 409.23 1.11 LC11_2 >10.0
    3-methoxy-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    500 3-Biphenyl-4-yl-3-[(2-chloro- 395.22 1.12 LC11_2 >10.0
    6-methyl-pyridine-4-
    carbonyl)-amino]-propionic
    acid
    501 3-Biphenyl-4-yl-3-[(6-chloro- 381.18 1.13 LC11_2 0.463
    pyridine-2-carbonyl)-amino]-
    propionic acid
    502 3-Biphenyl-4-yl-3-[(5-chloro- 397.18 1.01 LC11_2 >10.0
    6-hydroxy-pyridine-3-
    carbonyl)-amino]-propionic
    acid
    503 3-Biphenyl-4-yl-3-[(2-chloro- 381.18 1.09 LC11_2 >10.0
    pyridine-4-carbonyl)-amino]-
    propionic acid
    504 3-Biphenyl-4-yl-3-[(5-chloro- 381.45 1.09 LC11_2 >10.0
    pyridine-3-carbonyl)-amino]-
    propionic acid
    505 3-Biphenyl-4-yl-3-[(5-chloro- 411.2 1.14 LC11_2 >10.0
    6-methoxy-pyridine-3-
    carbonyl)-amino]-propionic
    acid
    506 (S)-3-[(3,6-Dichloro-pyridine- 353.11 1.03 LC11_2 8.48
    2-carbonyl)-amino]-3-o-tolyl-
    propionic acid
    507 (S)-3-[(2-Chloro-6-methyl- 331.17 1.02 LC11_2 >10.0
    pyridine-4-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    508 (S)-3-[(2-Chloro-6-methoxy- 349.18 1.07 LC11_2 >10.0
    pyridine-4-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    509 (S)-3-[(2,6-Dichloro-pyridine- 353.12 1.08 LC11_2 >10.0
    4-carbonyl)-amino]-3-o-tolyl-
    propionic acid
    510 (S)-3-[(6-Chloro-pyridine-2- 319.16 1.05 LC11_2 0.2049
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    511 (S)-3-[(5-Chloro-6-hydroxy- 333.14 0.88 LC11_2 >10.0
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    512 (S)-3-[(2-Chloro-pyridine-4- 317.16 0.99 LC11_2 >10.0
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    513 (S)-3-[(5-Chloro-pyridine-3- 319.17 0.98 LC11_2 >10.0
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    514 (S)-3-[(6-Chloro-pyrazine-2- 320.03 3.67 LC2 1.21
    carbonyl)-amino]-3-o-tolyl-
    propionic acid
    515 (S)-3-[(3,5-Diamino-6-chloro- 350.16 0.97 LC11_2 0.0871
    pyrazine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    516 3-Biphenyl-4-yl-3-{[5-chloro- 438.29 1.04 LC11_2 >10.0
    6-(2-hydroxy-ethylamino)-
    pyridine-3-carbonyl]-amino}-
    propionic acid
    517 (S)-3-[(5-Chloro-6-methoxy- 347.15 1.05 LC11_2 >10.0
    pyridine-3-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    518 (S)-3-[(2,5-Dichloro-pyridine- 351.11 1.01 LC11_2 >10.0
    3-carbonyl)-amino]-3-o-tolyl-
    propionic acid
    519 3-Biphenyl-4-yl-3-[(3,5- 412.19 1.07 LC11_2 0.563
    diamino-6-chloro-pyrazine-2-
    carbonyl)-amino]-propionic
    acid
    520 (S)-3-[(4-Chloro-3-methoxy- 347.16 1.01 LC11_2 >10.0
    pyridine-2-carbonyl)-amino]-
    3-o-tolyl-propionic acid
    521 3-(2-Chloro-phenyl)-3- 304.19 1.05 LC11_2 12.8
    [(pyrazine-2-carbonyl)-
    amino]-propionic acid
    522 3-(2-Chloro-phenyl)-3- 305.07 0.98 LC11_2
    [(pyridine-3-carbonyl)-
    amino]-propionic acid
    523 3-(2-Chloro-phenyl)-3- 305.08 1.12 LC11_2
    [(pyridine-2-carbonyl)-
    amino]-propionic acid
    524 3-(2-Chloro-phenyl)-3- 305.08 0.97 LC11_2 10.2
    [(pyridine-4-carbonyl)-
    amino]-propionic acid
    525 3-(2-Chloro-phenyl)-3-[(5- 318.17 1.09 LC11_2
    methyl-pyrazine-2-carbonyl)-
    amino]-propionic acid
    526 3-(2-Chloro-phenyl)-3-[(2- 319.09 0.94 LC11_2
    methyl-pyridine-4-carbonyl)-
    amino]-propionic acid
    527 3-(2-Chloro-phenyl)-3-[(6- 319.1 1.16 LC11_2 4.96
    methyl-pyridine-2-carbonyl)-
    amino]-propionic acid
    528 3-(2-Chloro-phenyl)-3-[(4- 319.1 1.16 LC11_2 5.81
    methyl-pyridine-2-carbonyl)-
    amino]-propionic acid
    529 3-(2-Chloro-phenyl)-3-[(4- 321.06 0.97 LC11_2 5.12
    hydroxy-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    530 3-(2-Chloro-phenyl)-3-[(3- 321.14 1.09 LC11_2 5.27
    fluoro-pyridine-2-carbonyl)-
    amino]-propionic acid
    531 3-(2-Chloro-phenyl)-3-[(6- 323.06 1.15 LC11_2 7.65
    fluoro-pyridine-2-carbonyl)-
    amino]-propionic acid
    532 3-(2-Chloro-phenyl)-3-[(4- 331.22 1.21 LC11_2 10.2
    ethyl-pyridine-2-carbonyl)-
    amino]-propionic acid
    533 3-(2-Chloro-phenyl)-3-[(4,6- 331.22 1.2 LC11_2 6.29
    dimethyl-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    534 3-(2-Chloro-phenyl)-3-[(4,6- 333.11 0.92 LC11_2
    dimethyl-pyridine-3-
    carbonyl)-amino]-propionic
    acid
    535 3-(2-Chloro-phenyl)-3-[(6- 335.08 1.07 LC11_2
    methylamino-pyrazine-2-
    carbonyl)-amino]-propionic
    acid
    536 3-(2-Chloro-phenyl)-3-[(2- 335.08 1.11 LC11_2 5.08
    methoxy-pyridine-4-
    carbonyl)-amino]-propionic
    acid
    537 3-(2-Chloro-phenyl)-3-[(6- 335.08 1.1 LC11_2
    methoxy-pyridine-3-
    carbonyl)-amino]-propionic
    acid
    538 3-(2-Chloro-phenyl)-3-[(6- 335.08 1.18 LC11_2
    methoxy-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    539 3-(2-Chloro-phenyl)-3-[(3- 335.09 1.03 LC11_2 >10.0
    methoxy-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    540 3-(2-Chloro-phenyl)-3-[(6- 339.02 1.18 LC11_2 1.6
    chloro-pyridine-2-carbonyl)-
    amino]-propionic acid
    541 3-(2-Chloro-phenyl)-3-[(3,6- 339.14 1.12 LC11_2
    difluoro-pyridine-2-carbonyl)-
    amino]-propionic acid
    542 3-(2-Chloro-phenyl)-3-[(3H- 345.06 1.0 LC11_2 10.8
    imidazo[4,5-b]pyridine-5-
    carbonyl)-amino]-propionic
    acid; compound with
    trifluoro-acetic acid
    543 3-(2-Chloro-phenyl)-3- 356.07 1.09 LC11_2
    [([1,8]naphthyridine-2-
    carbonyl)-amino]-propionic
    acid
    544 3-(2-Chloro-phenyl)-3- 356.07 1.08 LC11_2 11.1
    [([1,6]naphthyridine-2-
    carbonyl)-amino]-propionic
    acid
    545 3-[(2-Acetylamino-pyridine-4- 362.08 1.02 LC11_2
    carbonyl)-amino]-3-(2-
    chloro-phenyl)-propionic acid
    546 3-[(2-Amino-6-isopropyl- 363.12 1.15 LC11_2
    pyrimidine-4-carbonyl)-
    amino]-3-(2-chloro-phenyl)-
    propionic acid; compound
    with trifluoro-acetic acid
    547 (S)-3-{[6-(2-Fluoro-phenyl)- 365.29 1.75 LC X 0.345
    pyridine-2-carbonyl]-amino}-
    3-phenyl-propionic acid
    548 3-(2-Chloro-phenyl)-3-[(4,6- 366.07 1.24 LC X
    dimethoxy-pyrimidine-2-
    carbonyl)-amino]-propionic
    acid
    549 3-(2-Chloro-phenyl)-3-[(2,6- 366.08 1.19 LC X
    dimethoxy-pyrimidine-4-
    carbonyl)-amino]-propionic
    acid
    550 3-[(6-Chloro-5-methoxy- 369.03 1.19 LC X 1.08
    pyridine-2-carbonyl)-amino]-
    3-(2-chloro-phenyl)-propionic
    acid
    551 3-(2-Chloro-phenyl)-3-[(6- 371.08 0.96 LC X
    imidazol-1-yl-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    552 3-(2-Chloro-phenyl)-3-[(3,6- 371.1 1.18 LC X
    dichloro-pyridine-2-
    carbonyl)-amino]-propionic
    acid
    553 3-(2-Chloro-phenyl)-3-[(2- 374.11 0.96 LC X 11.1
    pyrrolidin-1-yl-pyridine-4-
    carbonyl)-amino]-propionic
    acid; compound with
    trifluoro-acetic acid
    554 3-(2-Chloro-phenyl)-3-[(6- 374.11 0.95 LC X
    pyrrolidin-1-yl-pyridine-3-
    carbonyl)-amino]-propionic
    acid; compound with
    trifluoro-acetic acid
    555 3-(2-Chloro-phenyl)-3-[(5- 374.13 1.01 LC11_2 >10.0
    pyrrolidin-1-yl-pyridine-3-
    carbonyl)-amino]-propionic
    acid; compound with
    trifluoro-acetic acid
    556 (S)-3-{[5-Chloro-6-(2- 376.22 0.92 LC11_2 >10.0
    hydroxy-ethylamino)-
    pyridine-3-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    557 3-[(2-Amino-6-isobutyl- 377.12 1.19 LC11_2 14
    pyrimidine-4-carbonyl)-
    amino]-3-(2-chloro-phenyl)-
    propionic acid
    558 (S)-3-{[6-(2-Fluoro-phenyl)- 379.33 1.8 LC X
    pyridine-2-carbonyl]-amino}-
    3-phenyl-butyric acid
    559 (S)-3-{[6-(2-Fluoro-phenyl)- 379.33 1.81 LC X 4.38
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    560 (S)-3-{[6-(2-Fluoro-phenyl)- 379.33 1.81 LC X 12.9
    pyridine-2-carbonyl]-amino}-
    3-m-tolyl-propionic acid
    561 (R)-3-{[6-(2-Fluoro-phenyl)- 379.34 1.79 LC X 5.33
    pyridine-2-carbonyl]-amino}-
    4-phenyl-butyric acid
    562 3-[(6-Bromo-pyridine-2- 381.04 1.2 LC11_2 2.1
    carbonyl)-amino]-3-(2-
    chloro-phenyl)-propionic acid
    563 3-(2-Chloro-phenyl)-3-[(6- 381.1 1.27 LC11_2 3.09
    phenyl-pyridine-2-carbonyl)-
    amino]-propionic acid
    564 3-(2-Chloro-phenyl)-3-[(3- 381.1 1.18 LC11_2
    phenyl-pyridine-2-carbonyl)-
    amino]-propionic acid
    565 3-(2-Chloro-phenyl)-3-[(4- 381.1 1.27 LC11_2 4.07
    phenyl-pyridine-2-carbonyl)-
    amino]-propionic acid
    566 3-(2-Chloro-phenyl)-3-[(5- 381.11 1.18 LC11_2 11.7
    phenyl-pyridine-3-carbonyl)-
    amino]-propionic acid
    567 (S)-3-{[6-(2-Chloro-phenyl)- 381.27 1.77 LC X 2.18
    pyridine-2-carbonyl]-amino}-
    3-phenyl-propionic acid
    568 3-[(5-Bromo-pyridine-3- 382.97 1.13 LC11_2
    carbonyl)-amino]-3-(2-
    chloro-phenyl)-propionic acid
    569 (S)-3-(3-Fluoro-phenyl)-3- 383.29 1.77 LC11_X 0.429
    {[6-(2-fluoro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    570 (S)-3-(2-Fluoro-phenyl)-3- 383.3 1.76 LC11_X 0.195
    {[6-(2-fluoro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    571 (S)-3-(4-Fluoro-phenyl)-3- 383.3 1.77 LC11_X 0.514
    {[6-(2-fluoro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    572 3-(2-Chloro-phenyl)-3- 388.15 1.03 LC11_2 >10.0
    [(3,4,5,6-tetrahydro-2H-
    [1,2′]bipyridinyl-4′-carbonyl)-
    amino]-propionic acid;
    compound with trifluoro-
    acetic acid
    573 3-(2-Chloro-phenyl)-3- 388.16 1.29 LC11_2
    [(3,4,5,6-tetrahydro-2H-
    [1,2′]bipyridinyl-6′-carbonyl)-
    amino]-propionic acid;
    compound with trifluoro-
    acetic acid
    574 3-(2-Chloro-phenyl)-3-[(6- 390.12 1.16 LC11_2
    morpholin-4-yl-pyridine-2-
    carbonyl)-amino]-propionic
    acid; compound with
    trifluoro-acetic acid
    575 3-(2-Chloro-phenyl)-3-[(4- 390.12 0.93 LC11_2
    morpholin-4-yl-pyridine-2-
    carbonyl)-amino]-propionic
    acid; compound with
    trifluoro-acetic acid
    576 3-(2-Chloro-phenyl)-3-[(2- 390.13 1.03 LC11_2
    morpholin-4-yl-pyridine-4-
    carbonyl)-amino]-propionic
    acid; compound with
    trifluoro-acetic acid
    577 (S)-3-[(6-Methoxy-biphenyl- 390.2 1.26 LC11— 0.414
    3-carbonyl)-amino]-3-o-tolyl-
    propionic acid
    578 (S)-3-[(3-Methoxy- 392.08 0.91 LC11— 7.54
    [2,3′]bipyridinyl-6-carbonyl)-
    amino]-3-o-tolyl-propionic
    acid
    579 3-[(2,6-Bis-dimethylamino- 392.14 1.01 LC11_2
    pyrimidine-4-carbonyl)-
    amino]-3-(2-chloro-phenyl)-
    propionic acid; compound
    with trifluoro-acetic acid
    580 (S)-3-{[6-(2-Chloro-phenyl)- 393.19 1.95 LC 11_X 15.6
    pyridine-2-carbonyl]-amino}-
    3-p-tolyl-propionic acid
    581 (S)-3-{[6-(2-Chloro-phenyl)- 395.17 1.94 LC 11_X 5.76
    pyridine-2-carbonyl]-amino}-
    3-phenyl-butyric acid
    582 (S)-3-{[6-(2-Chloro-phenyl)- 395.18 1.96 LC 11_X 0.16
    pyridine-2-carbonyl]-amino}-
    3-m-tolyl-propionic acid
    583 (R)-3-{[6-(2-Chloro-phenyl)- 395.29 1.81 LC 11_X >30.0
    pyridine-2-carbonyl]-amino}-
    4-phenyl-butyric acid
    584 (S)-3-{[6-(2-Fluoro-phenyl)- 395.31 1.74 LC X 0.54
    pyridine-2-carbonyl]-amino}-
    3-(4-methoxy-phenyl)-
    propionic acid
    585 3-(2-Chloro-phenyl)-3-[(6- 397.08 1.21 LC 11 8.67
    phenoxy-pyridine-3-
    carbonyl)-amino]-propionic
    acid
    586 (S)-3-{[6-(2-Chloro-phenyl)- 399.13 1.92 LC 11_X 0.339
    pyridine-2-carbonyl]-amino}-
    3-(2-fluoro-phenyl)-propionic
    acid
    587 (S)-3-{[6-(2-Chloro-phenyl)- 399.15 1.92 LC 11_X 7.35
    pyridine-2-carbonyl]-amino}-
    3-(3-fluoro-phenyl)-propionic
    acid
    588 (S)-3-{[6-(2-Chloro-phenyl)- 399.23 4.49 LC 11_X 0.107
    pyridine-2-carbonyl]-amino}-
    3-(4-fluoro-phenyl)-propionic
    acid
    589 3-(2-Chloro-phenyl)-3-{[6-(2- 399.26 1.8 LC X 4.89
    fluoro-phenyl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    590 (S)-3-(3-Chloro-phenyl)-3- 399.26 1.83 LC 11_X 0.339
    {[6-(2-fluoro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    591 (S)-3-(4-Chloro-phenyl)-3- 399.27 1.83 LC 11_X 0.322
    {[6-(2-fluoro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    592 3-(2-Chloro-phenyl)-3-[(1- 401.13 1.14 LC 11_2
    ethyl-3,6-dimethyl-1H-
    pyrazolo[3,4-b]pyridine-4-
    carbonyl)-amino]-propionic
    acid
    593 3-(2-Chloro-phenyl)-3-{[2- 404.14 1.17 LC 11_2
    (2,2-dimethyl-
    propionylamino)-pyridine-4-
    carbonyl]-amino}-propionic
    acid
    594 3-(2-Chloro-phenyl)-3-{[6- 405.1 1.14 LC 11_2
    (tetrahydro-pyran-4-yloxy)-
    pyridine-3-carbonyl]-amino}-
    propionic acid
    595 3-(2-Chloro-phenyl)-3-{[6-(4- 409.3 1.27 LC 11_2 1.42
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    596 3-(2-Chloro-phenyl)-3-{[6-(3- 411.1 1.27 LC 11_2 5.77
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    597 3-(2-Chloro-phenyl)-3-{[6-(2- 411.1 1.27 LC 11_2 1.45
    methoxy-phenyl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    598 3-[(6-Bromo-5-methoxy- 411.18 1.2 LC 11_2 1.46
    pyridine-2-carbonyl)-amino]-
    3-(2-chloro-phenyl)-propionic
    acid
    599 (S)-3-{[6-(2-Chloro-phenyl)- 411.29 1.77 LC 11_X 2.83
    pyridine-2-carbonyl]-amino}-
    3-(4-methoxy-phenyl)-
    propionic acid
    600 3-(2-Chloro-phenyl)-3-[(6- 413.14 1.19 LC 11_2
    cyclopropyl-1,3-dimethyl-1H-
    pyrazolo[3,4-b]pyridine-4-
    carbonyl)-amino]-propionic
    acid
    601 3-(2-Chloro-phenyl)-3-{[4- 415.05 1.18 LC 11_2 3.85
    (pyrimidin-2-ylsulfanyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    602 (S)-3-(4-Chloro-phenyl)-3- 415.09 1.94 LC 11_X 0.0623
    {[6-(2-chloro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    603 (S)-3-(3-Chloro-phenyl)-3- 415.12 1.98 LC 11_2 0.0803
    {[6-(2-chloro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    604 3-(2-Chloro-phenyl)-3-{[6-(2- 415.25 1.83 LC_X 0.345
    chloro-phenyl)-pyridine-2-
    carbonyl]-amino}-propionic
    acid
    605 (S)-3-(2,4-Dichloro-phenyl)- 433.24 1.9 LC 11_X 2.28
    3-{[6-(2-fluoro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    606 (S)-3-(2,3-Dichloro-phenyl)- 433.25 1.87 LC 11_X 3.93
    3-{[6-(2-fluoro-phenyl)-
    pyridine-2-carbonyl]-amino}-
    propionic acid
    607 (S)-3-{[6-(2-Fluoro-phenyl)- 433.31 1.83 LC_X 0.88
    pyridine-2-carbonyl]-amino}-
    3-(2-trifluoromethyl-phenyl)-
    propionic acid
    608 (S)-3-{[6-(2-Fluoro-phenyl)- 433.31 1.87 LC_X 6.27
    pyridine-2-carbonyl]-amino}-
    3-(4-trifluoromethyl-phenyl)-
    propionic acid
    609 (S)-3-{[6-(2-Fluoro-phenyl)- 433.32 1.85 LC_X 0.902
    pyridine-2-carbonyl]-amino}-
    3-(3-trifluoromethyl-phenyl)-
    propionic acid
    610 (S)-3-{[6-(2-Chloro-phenyl)- 449.07 2.01 LC 11_X 2.32
    pyridine-2-carbonyl]-amino}-
    3-(2,3-dichloro-phenyl)-
    propionic acid
    611 (S)-3-{[6-(2-Chloro-phenyl)- 449.09 2.05 LC 11_X 0.27
    pyridine-2-carbonyl]-amino}-
    3-(2,4-dichloro-phenyl)-
    propionic acid
    612 (S)-3-{[6-(2-Chloro-phenyl)- 449.13 1.98 LC 11_X 1.66
    pyridine-2-carbonyl]-amino}-
    3-(2-trifluoromethyl-phenyl)-
    propionic acid
    613 (S)-3-{[6-(2-Chloro-phenyl)- 449.16 2.02 LC 11_X 0.406
    pyridine-2-carbonyl]-amino}-
    3-(4-trifluoromethyl-phenyl)-
    propionic acid
    614 (S)-3-{[6-(2-Chloro-phenyl)- 449.16 2.0 LC 11_X 0.315
    pyridine-2-carbonyl]-amino}-
    3-(3-trifluoromethyl-phenyl)-
    propionic acid
    615 3-(2-Chloro-phenyl)-3-{[3- 459.13 1.06 LC 11_2 3.58
    (4,6-dimethoxy-pyrimidin-2-
    yloxy)-pyridine-2-carbonyl]-
    amino}-propionic acid
    616 3-(2-Chloro-phenyl)-3-[(6- 465.21 5.02 LC 11_2 10.4
    phenyl-2-piperidin-1-yl-
    pyrimidine-4-carbonyl)-
    amino]-propionic acid;
    compound with trifluoro-
    acetic acid
    617 (S)-3-{[6-Bromo-5-(3,3- 477.03 1.25 LC 11 0.1568
    dimethyl-2-oxo-butoxy)-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    618 (S)-3-{[5-(3,3-Dimethyl-2- 1.19 LC 11_2
    oxo-butoxy)-6-phenyl-
    pyridine-2-carbonyl]-amino}-
    3-o-tolyl-propionic acid
    (1) Mass spectroscopic characterization; observed mass number of the ion [(M + H)+], unless specified otherwise
    (2) Cathepsin A inhibitory activity determined in the pharmacological test “Cathepsin A inhibitory activity” described below.
    • Pharmacological Tests a) Cathepsin A Inhibitory Activity
  • Recombinant human cathepsin A (residues 29-480, with a C-terminal 10-His tag; R&D Systems, #1049-SE) was proteolytically activated with recombinant human cathepsin L (R&D Systems, #952-CY). Briefly, cathepsin A was incubated at 10 μg/ml with cathepsin L at 1 μg/ml in activation buffer (25 mM 2-(morpholin-4-yl)-ethanesulfonic acid (MES), pH 6.0, containing 5 mM dithiothreitol (DTT)) for 15 min at 37° C. Cathepsin L activity was then stopped by the addition of the cysteine protease inhibitor E-64 (N-(trans-epoxysuccinyl)-L-leucine-4-guanidinobutylamide; Sigma-Aldrich, #E3132; dissolved in activation buffer/DMSO) to a final concentration of 10 μM.
  • The activated cathepsin A was diluted in assay buffer (25 mM MES, pH 5.5, containing 5 mM DTT) and mixed with the test compound (dissolved in assay buffer containing (v/v) 3% DMSO) or, in the control experiments, with the vehicle in a multiple assay plate. After incubation for 15 min at room temperature, as substrate then bradykinin carrying an N-terminal ®Bodipy FL (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl) label (JPT Peptide Technologies GmbH; dissolved in assay buffer) was added to the mixture. The final concentration of cathepsin A was 833 ng/ml and the final concentration of labeled bradykinin 2 μM. After incubation for 15 min at room temperature the reaction was stopped by the addition of stop buffer (130 mM 2-(4-(2-hydroxy-ethyl)-piperazin-1-yl)-ethanesulfonic acid, pH 7.4, containing (v/v) 0.013% ®Triton X-100, 0.13% Coating Reagent 3 (Caliper Life Sciences), 6.5% DMSO and 20 μM ebelactone B (Sigma, #E0886)).
  • Uncleaved substrate and product were then separated by a microfluidic capillary electrophoresis on a LabChip® 3000 Drug Discovery System (12-Sipper-Chip; Caliper Life Sciences) and quantified by determination of the respective peak areas. Substrate turnover was calculated by dividing product peak area by the sum of substrate and product peak areas, and the enzyme activity and the inhibitory effect of the test compound thus quantified. From the percentage of inhibition of cathepsin A activity observed with the test compound at several concentrations, the inhibitory concentration IC50, i.e. the concentration which effects 50% inhibition of enzyme activity was, calculated. IC50 values of various example compounds are given in Table 1 in μM.
    • B) In Vivo Antihypertrophic and Renoprotective Activity
  • The in vivo pharmacological activity of the compounds of the invention can be investigated, for example, in the model of DOCA-salt sensitive rats with unilateral nephrectomy. Briefly, in this model unilateral nephrectomy of the left kidney (UNX) is performed on Sprague Dawley rats of 150 g to 200 g of body weight. After the operation as well as at the beginning of each of the following weeks 30 mg/kg of body weight of DOCA (desoxycorticosterone acetate) are administered to the rats by subcutaneous injection. The nephrectomized rats treated with DOCA are supplied with drinking water containing 1% of sodium chloride (UNX/DOCA rats). The UNX/DOCA rats develop high blood pressure, endothelial dysfunction, myocardial hypertrophy and fibrosis as well as renal dysfunction. In the test group (UNX/DOCA Test) and the placebo group (UNX/DOCA Placebo), which consist of randomized UNX/DOCA rats, the rats are treated orally by gavage in two part administrations at 6 a.m. and 6 p.m. with the daily dose of the test compound (for example 10 mg/kg of body weight dissolved in vehicle) or with vehicle only, respectively. In a control group (control), which consists of animals which have not been subjected to UNX and DOCA administration, the animals receive normal drinking water and are treated with vehicle only. After five weeks of treatment, systolic blood pressure (SBP) and heart rate (HR) are measured non-invasively via the tail cuff method. For determination of albuminuria and creatinine, 24 h urine is collected on metabolic cages. Endothelial function is assessed in excised rings of the thoracic aorta as described previously (W. Linz et al., JRAAS (Journal of the renin-angiotensin-aldosterone system) 7 (2006), 155-161). As a measure of myocardial hypertrophy and fibrosis, heart weight, left ventricular weight and the relation of hydroxyproline and proline are determined in excised hearts.

Claims (15)

1. A compound of formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them,
Figure US20140135328A1-20140515-C00012
wherein
A is selected from the group consisting of C(R1) and N;
D is selected from the group consisting of C(R2) and N;
E is selected from the group consisting of C(R3) and N;
L is selected from the group consisting of C(R4) and N;
wherein two of A, D, E, and L are N;
G is selected from the group consisting of R71—O—C(O)—, R72—N(R73)—C(O)— and tetrazol-5-yl;
R1 is selected from the group consisting of hydrogen, halogen, (C1-C6)-alkyl, HO, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m— and NC—;
R2 is selected from the group consisting of hydrogen, halogen, (C1-C7)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-CO—, (C1-C6)-alkyl-CO—HN—, —NR12R13, Het2′ (C3-C7)-cycloalkyl-CsH2s— and Ar—CsH2s—;
R3 is selected from the group consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-S(O)m—, Het4-(O)t—, —NR12R13, Het2, R11—O—, R12—N(R13)—C(O)—O—, Het2-C(O)—O— and NC—;
or R1 and R2 or R2 and R3 form pyridyl;
or R1 and R2 are —C((C1-C3)-alkyl)═N—N((C1-C3)-alkyl)-;
or R2 and R3 are —NH—CH═N—;
R4 is selected from the group consisting of hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, HO—, NR12R13, and Het2;
R10 is selected from the group consisting hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, HO—, —NR12R13, Het2, phenyl-CsH2s—(O)t—;
with the proviso that one of R1, R2, R3, R4 or R10 is a cyclic substituent;
s is 0, 1, 2 or 3;
t is 0 or 1;
R11 is selected from the group consisting of hydrogen, R14, (C3-C7)-cycloalkyl, Ar and Het3;
R12 and R13 are independently selected from hydrogen and R15;
R14 is (C1-C10)-alkyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, HO—, R16—O—, oxo, (C3-C7)-cycloalkyl, Ar, Het1, Het3, NC—, H2N—C(O)—, (C1-C4)-alkyl-NH—C(O)—, di((C1-C4)-alkyl)N—C(O)—, Het1-C(O)—, (C1-C4)-alkyl-C(O)—NH—, and (C1-C4)-alkyl-S(O)m—;
R15 is (C1-C6)-alkyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting halogen, HO—, and (C1-C6)-alkyl-O—;
R16 is (C1-C6)-alkyl, which is optionally substituted by one or more identical or different substituents selected from the group consisting of HO—, (C1-C4)-alkyl-O—, and NC—;
R30 is selected from the group consisting of R31, (C3-C7)-cycloalkyl,
R32—CuH2u— and Het3-CuH2u—, wherein u is an integer selected from the group consisting of 0, 1, 2 and 3;
R31 is (C1-C10)-alkyl, which is optionally substituted by one or two identical or different substituents selected from the group consisting of halogen, (C3-C7)-cycloalkyl, HO—, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S(O)m—, and NC—;
R32 is selected from the group consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle containing one, two or three identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C6)-alkyl, HO—, (C1-C6)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2—, (C1-C4)-alkyl-NH—S(O)2—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, (C1-C6)-alkyl-NH—, di((C1-C6)-alkyl)N—, (C1-C4)-alkyl-C(O)—NH—, (C1-C4)-alkyl-S(O)2—NH— and NC—, or substituted once by a phenyl ring or (C3-C7)-cycloalkyl ring;
R40 is selected from the group consisting of hydrogen and (C1-C4)-alkyl;
or R30 and R40 together are (CH2)x, which is optionally substituted by one or more identical or different (C1-C4)-alkyl substituents, wherein x is 2, 3, 4, or 5;
R50 is selected from the group consisting of hydrogen, (C1-C6)-alkyl, HO— and (C1-C6)-alkyl-O—;
R60 is selected from hydrogen and (C1-C6)-alkyl;
or R50 and R60 together are (CH2)y, which is optionally substituted by one or more identical or different (C1-C4)-alkyl substituents, wherein y is 2, 3, 4, or 5;
R71 is selected from hydrogen and (C1-C8)-alkyl, which is optionally substituted by one or more identical or different substituents selected from (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—;
R72 is selected from the group consisting of hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, —CH2—(CH2)b—(C3-C6)-cycloalkyl, Het4, and —(CH2)b-Het4, wherein alkyl or cycloalkyl is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, HO—, HOOC—, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-C(O)—O—, NC—, and N((C1-C4)-alkyl)2, and b is 0, 1 or 2;
R73 is selected from hydrogen and (C1-C6)-alkyl; or
R72 and R73, together with the nitrogen atom to which they are bonded, form a saturated 4-membered to 7-membered monocyclic heterocycle, which contain optionally one further ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C4)-alkyl, HO— and (C1-C4)-alkyl-O—;
Ar, independently of each other group Ar, is selected from the group consisting of phenyl and an aromatic 5-membered or 6-membered monocyclic heterocycle containing one, two, or three identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a ring carbon atom, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C6)-alkyl, HO—(C1-C6)-alkyl, Het4, —(CH2)x-phenyl, (C1-C6)-alkyl-O—, (C3-C7)-cycloalkyl-(CH2)x—O—, —CF3, —CO—(C1-C6)-alkyl, —NR12R13, Het2, —CO—NR12R13, CO-Het2, (C1-C6)-alkyl-S(O)m—, H2N—S(O)2— and NC—; and
wherein phenyl may be substituted by —CH═CH—CH═CH—, —O—CH2—O—, —O—CH2—CH2—O—, —O—CF2—O—, or —N((C1-C3)-alkyl)-CH═CH—;
Het1, independently of each other group Het1, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle containing a ring nitrogen atom via which Het1 is bonded, and optionally, one or two identical or different further ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O—, oxo, and NC—;
Het2 is a saturated 4-membered to 7-membered monocyclic heterocycle containing a ring nitrogen atom via which Het2 is bonded and optionally one further ring heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C4)-alkyl, HO—, and (C1-C4)-alkyl-O—;
Het3, independently of each other group Het3, is a saturated 4-membered to 7-membered monocyclic heterocycle containing one or two identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is bonded via a ring carbon atom and optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine, (C1-C4)-alkyl and oxo;
Het4, independently of each other group Het4, is a saturated or unsaturated 4-membered to 8-membered monocyclic heterocycle containing one to four ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C4)-alkyl, HO—, (C1-C4)-alkyl-O—, oxo, and NC—;
m is independently 0, 1, or 2;
wherein all cycloalkyl groups, independently of each other, are optionally substituted by one or more identical or different substituents selected from fluorine and (C1-C4)-alkyl;
wherein all alkyl, CsH2s, CuH2u, (CH2)x, and (CH2)y groups, independently of each other, and independently of any other substituents, are optionally substituted by one or more fluorine substituents.
2. A compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 1,
wherein
G is selected from the group consisting of R71—O—C(O)— and R72—N(R73)—C(O)—;
R30 is R32—CuH2u—, wherein u is 0 or 1;
R32 is selected from the group consisting of phenyl and an aromatic 6-membered monocyclic heterocycle containing one or two nitrogen atoms as ring heteroatoms, wherein the phenyl and the heterocycle are optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C6)-alkyl, HO—, (C1-C6)-alkyl-O—, —O—CH2—O—, —O—CF2—O, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, di((C1-C6)-alkyl)N—, (C1-C4)-alkyl-C(O)—NH—, and NC—, or substituted once by a phenyl ring or (C3-C7)-cycloalkyl ring; and
R40 is hydrogen.
3. A compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 1,
wherein
G is R71—O—C(O)—;
R30 is R32—CuH2u—, wherein u is 0;
R32 is phenyl, wherein the phenyl is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen, (C1-C6)-alkyl, HO—, (C1-C6)-alkyl-O—, —O—CH2—O—, —O—CF2—O—, (C1-C6)-alkyl-S(O)m—, di((C1-C4)-alkyl)N—S(O)2—, H2N—, di((C1-C6)-alkyl)N—, (C1-C4)-alkyl-C(O)—NH—, and NC—, or substituted once by a phenyl ring or (C3-C7)-cycloalkyl ring; and
R40 is hydrogen.
4. A compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 1,
wherein
R50 and R60 are both hydrogen.
5. A compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 1, selected from the subformulae:
Figure US20140135328A1-20140515-C00013
wherein R1, R2, R3, R4, R10, R30, R40, R50, and R60 are as defined in claim 1.
6. A compound of the formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 1,
wherein
R3 is R11—O—, wherein R11 is as defined in claim 1.
7. A compound of the formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 6,
wherein
R11 is hydrogen or (C1-C10)-alkyl.
8. A compound of the formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 1,
wherein
R3 is —O—CH3.
9. A compound of the formula I, or a physiologically acceptable salt thereof, or a physiologically acceptable solvate of any of them, as claimed in claim 1, selected from:
(S)-3-[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
3-Biphenyl-4-yl-3-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-propionic acid
(S)-3-[(6-Methylamino-pyrazine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
(S)-3-[(5-Methyl-pyrazine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
(S)-3-[(6-Chloro-pyrazine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
3-(2-Chloro-phenyl)-3-[(pyrazine-2-carbonyl)-amino]-propionic acid
3-(2-Chloro-phenyl)-3-[(5-methyl-pyrazine-2-carbonyl)-amino]-propionic acid
3-(2-Chloro-phenyl)-3-[(6-methylamino-pyrazine-2-carbonyl)-amino]-propionic acid
(S)-3-[(2,6-Dimethoxy-pyrimidine-4-carbonyl)-amino]-3-o-tolyl-propionic acid
(S)-3-[(2,6-Bis-dimethylamino-pyrimidine-4-carbonyl)-amino]-3-o-tolyl-propionic acid
(S)-3-[(4,6-Dimethoxy-pyrimidine-2-carbonyl)-amino]-3-o-tolyl-propionic acid
(S)-3-[(2-Amino-6-isobutyl-pyrimidine-4-carbonyl)-amino]-3-o-tolyl-propionic acid
(S)-3-[(2,6-Dimethyl-pyrimidine-4-carbonyl)-amino]-3-o-tolyl-propionic acid
3-[(2-Amino-6-isopropyl-pyrimidine-4-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid
3-(2-Chloro-phenyl)-3-[(4,6-dimethoxy-pyrimidine-2-carbonyl)-amino]-propionic acid
3-(2-Chloro-phenyl)-3-[(2,6-dimethoxy-pyrimidine-4-carbonyl)-amino]-propionic acid
3-[(2-Amino-6-isobutyl-pyrimidine-4-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid
3-[(2,6-Bis-dimethylamino-pyrimidine-4-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid and
3-(2-Chloro-phenyl)-3-[(6-phenyl-2-piperidin-1-yl-pyrimidine-4-carbonyl)-amino]-propionic acid.
10. A process for preparing the compound of formula I or a physiologically acceptable salt thereof or a physiologically solvate of any of them as claimed in claim 1, comprising reacting a compound of the formula II with a compound of the formula III,
Figure US20140135328A1-20140515-C00014
wherein the groups A, D, E, L, G, R10, R30, R40, R50 and R60 in the compounds of the formulae II and III are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group, and the group J in the compound of the formula II is HO—, (C1-C4)-alkyl-O— or halogen.
11. A pharmaceutical composition comprising the compound of claim 1 or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them.
12. The pharmaceutical composition of claim 11, further comprising a pharmaceutically acceptable carrier.
13. A method of treating heart failure, congestive heart failure, cardiomyopathy, myocardial infarction, left ventricular dysfunction, cardiac hypertrophy, valvular heart diseases, hypertension, atherosclerosis, peripheral arterial occlusive disease, restenosis, vasvular permeability disorders, treatment of edema, thrombosis, rheumatoid arthritis, osteoarthritis, renal failure, cystic fibrosis, chronic bronchitis, chronic obstructive pulmonary disease, asthma, immunological diseases, diabetic complications, fibrotic diseases, pain, ischemia or reperfusion damage or neurodegenerative diseases, or for cardioprotection or renoprotection or as a diuretic (stand-alone treatment or in combination with established diuretics) in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 11.
14. A compound of claim 1 selected from:
Figure US20140135328A1-20140515-C00015
wherein R1, R2, R3, R10, R30, R40, R50, and R60 are as defined in claim 1.
15. A compound of claim 1 selected from:
Figure US20140135328A1-20140515-C00016
wherein R1, R2, R3, R4, R10, R30, R40, R50, and R60 are as defined in claim 1.
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